Found 2 matching records:
Displaying record number 2586
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MAb ID |
3BNC117 (3BNC117dRU3) |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
Env |
Epitope |
|
Subtype |
B |
Ab Type |
gp120 CD4bs |
Neutralizing |
P (tier 2) View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG) |
Patient |
Patient 3 |
Immunogen |
HIV-1 infection |
Country |
United States |
Keywords |
acute/early infection, antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autoantibody or autoimmunity, autologous responses, binding affinity, broad neutralizer, CD4+ CTL, chimeric antibody, chronic infection, class I down-regulation by Nef, co-receptor, complement, computational prediction, contact residues, early treatment, effector function, elite controllers and/or long-term non-progressors, escape, genital and mucosal immunity, glycosylation, HAART, ART, HIV reservoir/latency/provirus, immunoprophylaxis, immunotherapy, junction or fusion peptide, mutation acquisition, neutralization, polyclonal antibodies, review, structure, subtype comparisons, supervised treatment interruptions (STI), vaccine antigen design, vaccine-induced immune responses, viral fitness and/or reversion |
Notes
Showing 114 of
114 notes.
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3BNC117: This review on antibody mediated cellular cytotoxicity (ADCC) effector functions of anti-HIV-1 antibodies discusses the association between the conformational state of HIV antigen, Env, and binding of either bnAbs or nnAbs (non-neutralizing antibodies) to it and their consequent Fc-mediated ADCC. While bnAbs tend to recognize the 'closed' trimeric State 1 conformation of Env, nnAbs and HIV+ sera bind States 2 and 3 of Env brought to its open conformation by interaction with the host CD4 molecule. Nef/Vpu-induced down regulation of membrane-bound CD4 (and also HLA, Env, BST-2, and NKG2DL) in HIV-infected cells therefore keeps Env in State 1 and these cells, reminiscent of the HIV latent reservoir, are susceptible to bnAb neutralization as well as ADCC. The use of CD4 mimetics (CD4mc), however, can mimic the interaction of CD4 with Env and bring it to its open, nnAb-binding state, after successive exposure of conserved epitopes in the coreceptor binding site (CoRBS) and anti cluster A to nnAbs. Therefore different ADCC-measuring assays are discussed with particular reference to the target cell being either HIV-infected and conducive to bnAb measurements or Env gp120 coated and a measure of nnAb ADCC. The inaccuracies introduced by bystander un-infected cells exposed to shed gp120 are also discussed. Antibodies A32, C11, N5i5 and 2.2c bind to the CD4-induced cluster A epitope on Env. While bnAbs VRC01, 3BNC117, PGT151, 8ANC195, PG9, PG16, PGT121, PGT126 have different binding regions all on closed State 1 of Env and elicit ADCC, the MPER set of 10E8, 4E10 and 2F5 recognize State 1 but do not result in potent ADCC. Studies have shown that some CD4BS bnAbs like b12 protect macaques from SHIV challenge, and 3BNC117 control HIV replication in humanized mice.
Richard2018
(CD4+ CTL, class I down-regulation by Nef, co-receptor, effector function, review)
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3BNC117: Eighty clusters of overlapping epitopes that could bind to MHC Class II HLA-DR1*01:01 (DR1) allele were identified by LC-MS/MS using a cell-free processing system that incorporated soluble DR1, HLA-DM (DM), cathepsins, and full-length protein antigens (Gag, Pol, Env, Vif, Tat, Rev, and Nef). Sixteen of Env CD4+ T cell epitopes identified in this study, which were primarily located in the vicinity of the gp120/gp41 interface or the CD4bs, were assessed for overlap with bnAb binding footprints. 5/16 overlapped with the binding footprint of CD4bs-targeting bnAb 3BNC117: EEE267-283 (EEEVMIRSENITNNAKN), EQF351-371 (EQFGNNKTIIFKQSSGGDPEIV), SDN274-287 (SDNFTNNAKTIIVQ), KSI305-317 (KSIHIGPGRAF), and ETF466-476 (ETFRPGGGDMR). The first 2 were identified as glycosylated forms, while the latter 2 were identified as unglycosylated forms, and SDN274-287 was identified with both glycosylated and unglycosylated forms.
Sengupta2023
(antibody binding site)
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3BNC117: Unbiased sequence analysis of B-cell receptor repertoirs from 57 uninfected and 46 chronic participants were used to inform a probabalistic model of bnAb likelihood of development. The lower the bnAb probability of development, the higher the predictive neutralization capacity and actual potency. The IGoR (Inference and Generation of Repertoires) tool was used to predict CDRH3 generation probability (Pgen) and point mutation accumulation probability (PSHM), and their combined probability score, S, along with giving a method of ranking bnAbs, was highly predictive of neutralization potency. Despite CDRH3 length and number of mutations being a strong determinant of bnAb probability, 3BNC117 was one Ab that did not increased SHM, but is a potent bnAb. Untreated chronic individuals had a very slight correlation with longer CDRH3s but breadth of neutralization was not correlated with presence or absence of (ART) treatment. Overall, though, there is no difference in probability of bnAb development and generation with chronic disease state.
Kreer2023
(mutation acquisition, neutralization, computational prediction, antibody sequence, chronic infection)
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3BNC117: This preview summarizes the findings of Doud2017, Dingens2017, and Dingens2019 where all possible point mutation escapes from binding nAbs were mapped using a screen of single amino acid changes of soluble Env ectodomain that were then grown and exposed to bnAbs. A loss of interaction/binding to the bnAb suggested neutralization resistant Env and these were deep sequenced, giving an atlas of escape pathways the virus might take. Escape mutants were found to mostly overlap with the 5 structural epitopes (antigen binding regions) of Env even though many of them are not reported in nature. Two additional sets of mutations were found in (1) contact residues that do not affect neutralization and (2) residues outside the 5 structural epitopes. These studies will provide a third characteristic to add to successful bnAb generation besides breadth and potency - "non-susceptibility to escape". Combination therapy trials like those of VRC01 and 3BNC117, both CD4bs bnAbs, would also benefit from an understanding of their antigenic escape profile.
Ward2019
(review)
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3BNC117: The study describes the generation, crystal structure, and immunogenic properties of a native-like Env SOSIP trimer based on a group M consensus (ConM) sequence. A crystal structure of ConM SOSIP.v7 trimer together with nAbs PGT124 and 35O22 revealed that ConM SOSIP.v7 is structurally similar to other Env trimers. In rabbits, the ConM SOSIP trimer induced serum nAbs that neutralized the autologous Tier 1A virus (ConM from 2004) and a related Tier 1B ConS virus (ConM from 2001). These responses target the trimer apex and were enhanced when the trimers were presented on ferritin nanoparticles. The neutralization of ConM and ConS pseudoviruses was tested against a large panel of nAbs and non-nAbs (2219, 2557, 3074, 3869, 447-52D, 830A, 654-30D, 1008-30D, 1570D, 729-30D, F105, 181D, 246D, 50-69D, sCD4, VRC01, 3BNC117, CH31, PG9, PG16, CH01, PGDM1400, PGT128, PGT121, 10-1074, PGT151, VRC43.01, 2G12, DH511.2_K3, 10E8, 2F5, 4E10); most nAbs were able to neutralize these pseudoviruses. Soluble ConM trimers were able to weakly activate B cells expressing PGT121 and PG16 BCRs but were inactive against those expressing VRC01 and PGT145. In contrast, at the same molar amount of trimers, the ConM SOSIP.v7-ferritin nanoparticles activated all 4 B cells efficiently. Binding of bnAbs 2G12 and PGT145 and non-nAbs F105 and 19b to ConM SOSIP.v7 trimer and SOSIP showed that the ferritin-bound trimer bound more avidly than the soluble trimer. This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences, and such immunogens might be suitable vaccine components to prime and/or boost desirable nAb responses.
Sliepen2019
(neutralization, vaccine antigen design)
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3BNC117: A SHIV carrying a highly neutralization-sensitive Env (SHIVCNE40) was passaged in macaques. SHIVCNE40 developed enhanced replication kinetics associated with neutralization resistance against autologous serum, CD4-Ig, and several nAbs (17b, 3BNC117, N6, PGT145, PGT121, PGT128, 35O22, 2F5, 10E8). A gp41 substitution, E658K, was the major determinant for this resistance. Structural modeling and functional verification indicate that the substitution disrupts an intermolecular salt bridge with the neighboring protomer, thereby promoting fusion and facilitating immune evasion. This effect is applicable across many HIV-1 viruses of diverse subtypes. These results highlight the critical role of gp41 in shaping the neutralization profile and conformation of Env during viral adaptation. The unique intermolecular salt bridge could potentially be utilized for rational vaccine design involving more stable HIV-1 Env trimers.
Wang2019
(mutation acquisition, neutralization, structure)
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3BNC117: A panel of 30 contemporary subtype B pseudoviruses (PSVs) was generated. Neutralization sensitivities of these PSVs were compared with subtype B strains from earlier in the pandemic using 31 nAbs (PG9, PG16, PGT145, PGDM1400, CH02, CH03, CH04, 830A, PGT121, PGT126, PGT128, PGT130, 10-1074, 2192, 2219, 3074, 3869, 447-52D, b12, NIH45-46, VRC01, VRC03, 3BNC117, HJ16, sCD4, 10E8, 4E10, 2F5, 7H6, 2G12, 35O22). A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 nAbs for the contemporary, as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the nAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A metaanalysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.
Wieczorek2023
(neutralization, viral fitness and/or reversion)
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3BNC117: This study designed and expressed scFv versions of 4 HIV bnAbs prioritized for clinical testing: CAP256-VRC26.25 (V2-apex), PGT121 (V3-glycan supersite), 3BNC117 (CD4 binding site), and 10E8v4 (MPER). A 15- or 18-amino-acid glycine-serine linker between the heavy- and light-chain fragments provided adequate levels of scFv expression. When tested against a 45-multi-subtype virus panel, all 4 scFv retained good neutralizing activity, although there was some loss of function compared to the parental IgGs. Remarkably, 10E8v4-scFv maintained 100% breadth with only a minor reduction in potency. For CAP256-VRC26.25, there was a significant 138-fold loss of potency that was in part related to differential interaction with charged amino acids at positions 169 and 170 in the V2 epitope. Potency was reduced for the 3BNC117-scFv (13-fold) and PGT121-scFv (4-fold) among viruses lacking the N276 and N332 glycans, respectively, and in viruses with a longer V1 loop for PGT121-scFv. This suggested that scFvs interact with their epitopes in subtly different ways, with variation at key residues affecting scFv neutralization more than the corresponding IgGs. Overall, scFv of clinically relevant bNAbs had significant neutralizing activity, indicating that they could be considered for passive immunization.
vanDorsten2020
(neutralization, immunotherapy)
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3BNC117:This study identified a B cell lineage of bNAbs in an HIV-1 elite post-treatment controller (ePTC; donor: PTC-005002). Circulating viruses in PTC escaped bNAb pressure but remained sensitive to autologous neutralization by other Ab populations. 3BNC117 was used as a reference control IgG. Neutralizing activity of EPTC112 was evaluated in the presence and absence of 3BNC117.
Molinos-Albert2023
(antibody interactions)
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3BNC117: A panel of 58 mAbs was cloned from a rhesus macaque immunized with envelope glycoprotein immunogens developed from HIV-1 clade B-infected human donor VC10014. Neutralizing mAbs predominantly targeted linear epitopes in the V3 region in the cradle orientation (V3C), with others targeting the V3 ladle orientation (V3L), the CD4 binding site, C1, C4, or gp41. Nonneutralizing mAbs bound C1, C5, or undetermined gp120 conformational epitopes. Neutralization potency strongly correlated with the magnitude of binding to infected primary macaque splenocytes and to the level of ADCC, but did not correlate with ADCP. MAbs were traced to 23 of 72 functional IgHV germline alleles. Neutralizing V3C mAbs displayed minimal nucleotide SHM in the H chain V region (3.77%), indicating that relatively little affinity maturation was needed to achieve in-clade neutralization breadth. This study underscores the polyfunctional nature of vaccine-elicited tier 2-neutralizing V3 Abs and demonstrates partial reproduction of a human donor’s Ab response through nonhuman primate vaccination. Several previously-isolated mAbs were used in binding assays: b12, VRC01, N6, 3BNC117, 2558, 2219, 1006-15D, 447-52D, 10-1074, 830A, 2F5, F240, PGDM1400, 2219.
Spencer2021
(vaccine antigen design, binding affinity)
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3BNC117: Two conserved tyrosine (Y) residues within the V2 loop of gp120, Y173 and Y177, were mutated individually or in combination, to either phenylalanine (F) or alanine (A) in several strains of diverse subtypes. In general, these mutations increased neutralization sensitivity, with a greater impact of Y177 over Y173 single mutations, of double over single mutations, and of A over F substitutions. The Y173A Y177A double mutation in HIV-1 BaL increased sensitivity to most of the weakly neutralizing MAbs tested (2158, 447-D, 268-D, B4e8, D19, 17b, 48d, 412d) and even rendered the virus sensitive to non-neutralizing antibodies against the CD4 binding site (F105, 654-30D, and b13). In the case of V2 mAb 697-30D, residue Y173 is part of its epitope, and thus abrogates its binding and has no effect on neutralization; the Y177A mutant alone did increase neutralization sensitivity to this mAb. When the double mutant was tested against bnAbs, there was a large decrease in neutralization sensitivity compared to WT for many bnAbs that target V1, V2, or V3 (PG9, PG16, VRC26.08, VRC38, PGT121, PGT122, PGT123, PGT126, PGT128, PGT130, PGT135, VRC24, CH103). The double mutation had lesser or no effect on neutralization by one V3 bnAb (2G12) and by most bnAbs targeting the CD4 binding site (VRC01, VRC07, VRC03, VRC-PG04, VRC-CH31, 12A12, 3BNC117, N6), the gp120-gp41 interface (35O22, PGT151), or the MPER (2F5, 4E10, 10E8).
Guzzo2018
(antibody binding site, neutralization)
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3BNC117: This study explored the basis of the neutralization resistance of tier 3 virus 253-11 (subtype CRF02_AG). Virus 253-11 was resistant to neutralization by 17b, b12, VRC03, F105, SCD4, CH12, Z13e1, PG16, PGT145, 2G12, PGT121, PGT126, PGT128, PGT130, 39F, F240, and 35O22; the virus was sensitive to 3BNC117, NIH45-46G54W, VRC01, 10E8, 2F5, 4E10, PG9, VRC26.26, 10-1074, and PGT151. Virus 253-11 was strikingly resistant to most tested antibodies that target V3/glycans, despite possessing key potential N-linked glycosylation sites, especially N301 and N332, needed for the recognition of this class of antibodies. The resistance of 253-11 was not associated with an unusually long V1/V2 loop, nor with polymorphisms in the V3 loop and N-linked glycosylation sites. The 253-11 MPER was rarely recognized by sera, but was more often recognized in a chimera consisting of a HIV-2 backbone with the 253-11 MPER, suggesting steric or kinetic hindrance of the MPER. Mutations in the 253-11 MPER previously reported to increase the lifetime of the prefusion Env conformation (Y681H, L669S), decreased the resistance of 253-11 to several mAbs, presumably destabilizing its otherwise stable, closed trimer structure. A crystal structure of a recombinant 253-11 SOSIP trimer revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact form around the trimer axis.
Moyo2018
(neutralization, structure)
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3BNC117: This study assessed the ability of single bNAbs and triple bNAb combinations to mediate polyfunctional antiviral activity against a panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies in nonhuman primate models. Most bnAbs assayed were capable of mediating both neutralizing and nonneutralizing effector functions (ADCC and ADCP) against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs was highly strain dependent. Several triple bNAb combinations were identified comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. In assays using the transmitted/founder SHIV.C.CH505, there was a correlation between the neutralization potencies and nonneutralizing effector functions of bnAbs: 3BNC117 was positive for neutralization, ADCC, and binding to infected cells.
Berendam2021
(effector function, neutralization, binding affinity, broad neutralizer)
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3BNC117: The VRC01 Antibody Mediated Prevention (AMP) vaccine trials (2016-2020) showed that passively administered bnAbs could prevent HIV-1 acquisition of bnAb-sensitive viruses. Viruses isolated from AMP participants who acquired infection during the study were used to make a panel of 218 HIV-1 pseudoviruses. The majority of viruses identified were clade B and C, with clades A, D, F, G and recombinants present at lower frequencies. BnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10–1074 and 10E8v4) were tested for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998–2010), the AMP clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best antibody mixture against clade C viruses, and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. The AMP placebo virus panel represents a resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs.
Mkhize2023
(assay or method development, neutralization, immunotherapy)
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3BNC117: Cryo-electron microscopy (EM) of the cleaved, soluble SOSIP gp140 trimer complexed with CD4bs-binding bnAb PGV04 was studied at 5.8Å, facilitating study of Env V1/V2, V3, HR1 and HR2 domains and some shielding glycans. This provides further information on trimer assembly, gp120-gp41 interactions and the three-dimensional CD4bs epitope cluster. For instance, acidic residues in framework region 3 in the heavy chain (HFR3) of CD4bs antibodies 3BNC117 (also 3BNC60), VRC03 and VRC06 interact with basicresidues on an adjacent protomer.
Lyumkis2013
(vaccine antigen design, structure)
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3BNC117: To characterize the persistence and phenotypic properties of HIV Env over time, blood and lymphoid samples were obtained at 2 timepoints from 8 people with HIV on suppressive ART. Single genome amplification and sequencing was performed on env to understand genetic diversity clonal expansion. A subset of envs were used to generate pseudovirus particles to assess sensitivity to autologous plasma IgG and bnAbs, and neutralization was assayed against a panel of 5 bnAbs (VRC01, 10E8, PGT121, 10-1074, 3BNC117) and the trispecific N6/PGDM1400x10E8. Identical env sequences indicating clonal expansion persisted between timepoints and within multiple T-cell subsets. At both timepoints, CXCR4-tropic (X4) Envs were more prevalent in naive and central memory cells; the proportion of X4 Envs did not significantly change in each subset between timepoints. Autologous purified plasma IgG showed variable neutralization of Envs, with no significant difference in neutralization between R5 and X4 Envs. X4 Envs were more sensitive to neutralization with clinical bnAbs, with CD4-binding site bnAbs demonstrating high breadth and potency against Envs. These data suggest the viral reservoir was predominantly maintained over time through proliferation of infected cells. The humoral immune response to Envs within the latent reservoir was variable between persons. The study also found that coreceptor usage can influence bNAb sensitivity and may need to be considered for future bNAb immunotherapy approaches.
Gartner2023
(co-receptor, neutralization, HAART, ART, HIV reservoir/latency/provirus, polyclonal antibodies)
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3BNC117: N-linked glycosylation of antibodies can increase their chemical heterogeneity, complicating their manufacture. VRC01-like antibodies were assessed for the presence of light chain (LC) glycosylation, with some showing the presence of LC glycosylation (N6, VRC01, 3BNC117, VRC-CH31,) and some not (12A12, VRC18, VRC-PG04, VRC-PG20, VRC23, DRVIA7). This study developed a method to remove variable domain (Fv) glycans from nAbs, and used this method to develop engineered versions of 4 antibodies (VRC26.25, N6, PGT121, and VRC07-523).
Chuang2020
(assay or method development, glycosylation)
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3BNC117: Some CD4-binding site Abs have greater env trimer binding due to quaternary contacts. This study engrafted the extended heavy-chain framework region 3 (FR3) loop of VRC03, which mediates quaternary interaction, onto several potent bnAbs, enabling them to reach an adjacent gp120 protomer. The interactive quaternary surface was delineated by solving the crystal structure of 2 of the chimeric antibodies. Chimerization enhances the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. Compared to unmodified antibodies, the chimeric antibodies displayed lower autoreactivity and prolonged in vivo half-life in huFcRn mice and macaques. Thus, paratope engraftment may be used to expand the epitope repertory of natural antibodies, improving their functionality. 3BNC117-FR3-03 had less potent neutralization than 3BNC117. In two assays of autoreactivity, 3BNC117 was mildly autoreactive in one assay, while the chimera was not autoreactive in either assay.
Liu2019
(autoantibody or autoimmunity, neutralization)
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3BNC117: This paper comprehensively defined the effect of every viable single aa mutation in the ectodomain and transmembrane domain of BG505.T332N Env on binding by 9 individual bnAbs targeting 5 epitope classes (VRC01, 3BNC117, PGT121, 10-1074, PG9, PGT145, PGT151, VRC34.01, and 10E8), as well as by a mixture of 3BNC117 and 10-1074. Escape mutations mostly occurred in a small subset of structurally-defined contacts within <4 Å and at sites within 5-10 Å of the Ab. Escape from both CD4bs-targeting bnAbs, VRC01 and 3BNC117, occurred at sites including 197 (PNGS), 279 (loop D) and 369 (CD4 binding loop), but there were also Ab-specific differences. Env sites with the largest cumulative mutational impact on 3BNC117 binding were N197, K207, R304, Y318 and G471. These last 3 sites also had modest escape effects with the equal mixture of 3BNC117 and 10-1074. See LANL Features and Contacts database for more details.
Dingens2019
(antibody binding site, escape, contact residues)
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3BNC117: This study aimed to define properties shared by transmitted viruses by comparing antigenic and functional properties of envelope glycoproteins of viral variants isolated during primary infection in 27 patients belonging to 8 transmission clusters. The neutralization of the 27 pseudotyped viruses was assayed with 8 human bnAbs targeting various regions of the virus. The infectious properties of the viruses was assessed by measuring their infectivity and sensitivity to entry inhibitors. Transmitted viruses from the same transmission chain shared many properties, including similar neutralization profiles, sensitivity to inhibitors, and infectivity. All transmitted viruses were CCR5-tropic, sensitive to maraviroc, and resistant to soluble forms of CD4, irrespective of cluster. They were also generally sensitive to bnAbs that target V3 (10-1074, PGT121), CD4bs (3BNC117, NIH45-46G54W), and MPER region (10E8), suggesting that the loss of these epitopes may affect a virus’s capacity to be transmitted. The viruses were somewhat less sensitive to bnAbs targeting the V1V2 region (PG9, PGT145) and gp120/gp41 interface (8ANC195). These data suggest that the transmission bottleneck is governed by selective forces.
Beretta2018
(neutralization, acute/early infection)
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3BNC117: A recombinant native-like Env SOSIP trimer, AMC009, was developed based on viral founder sequences of elite neutralizer H18877. The subtype B AMC009 Env was defined as a Tier 2 virus based on a neutralization assay against well known nAbs (VRC01, 3BNC117, CH31, CH01, PG9, PG16, PGDM1400, 10-1074, PGT128, PGT121, PGT151, VRC34.01, 2G12, 2F5, 4E10, DH511.2.K3_4, 10E8, and the mAb mixture CH01-31).The AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bnAb epitopes. Its overall structure was similar to that of BG505 SOSIP.664, and it resembled one from another elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, AMC009 trimers did not induce autologous neutralizing antibody responses efficiently, while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the nAb activity from rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers.
Schorcht2020
(neutralization, vaccine-induced immune responses, structure)
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3BNC117: The study looked at the neutralization of subtype C Env sequences from 9 South African individuals followed longitudinally. A total of 43 Env sequences were cloned and assayed for neutralization by 12 bnAbs of various binding types (VRC07-LS, N6.LS, VRC01, PGT151, 10-1074 and PGT121, 10E8, 3BNC117, CAP256.VRC26.25, 4E10, PGDM1400, and N123-VRC34.01). Features associated with resistance to bNAbs were higher potential glycosylation sites, relatively longer V1 and V4 domains, and known signature mutations. The study found significant variability in the breadth and potency of bnAbs against circulating HIV-1 subtype C envelopes. In particular, VRC07-LS, N6.LS, VRC01, PGT151, 10-1074, and PGT121 display broad activity against subtype C variants. The results suggest that these 6 bnAbs are potent antibodies that should be considered for future antibody therapy and treatment studies targeting HIV-1 subtype C.
Mandizvo2022
(glycosylation, mutation acquisition, neutralization, immunotherapy)
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3BNC117: Structural characterization of macaque vaccine-induced mAbs Ab1303 and Ab1573 revealed a CD4bs binding mechanism that requires an occluded-open Env trimer conformation, similar to what has been observed for mAb b12. In a BG505 Env trimer binding competition assay, CD4bs-targeting 3BNC117 Fab competed substantially with both Ab1303 and Ab1573.
Yang2022
(antibody interactions)
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3BNC117: A macaque sequential immunization protocol with increasingly native-like V3-glycan-targeting Env trimers multimerized onto virus-like particles elicited multiple on-target mAbs with heterologous, yet generally weak, neutralization activity and minimal protection in a subsequent intrarectal heterologous challenge with SHIVDH12-V3AD8. The priming immunogen was RC1-4fill (clade A/E, RC1 with 4 additional glycans), a low affinity Env trimer with additional glycans to facilitate V3-glycan targeting and mask BG505 glycan hole, while the boosting immunogens were 11MUTB-4fill (clade A/E), B41-5MUT or B41 wildtype (clade B), AMC011/Du422 (clade B/C), and consensus group M/consensus clade C Env trimers. In a RC1 binding assay, 3BNC117 Fab competed substantially with bnAb IOMA and moderately with isolated macaque mAbs (Ab1303, Ab1368, Ab1456, Ab1461 and Ab1573), a shared PGT121/10-1074 inferred germline precursor, bnAbs IOMA and 8ANC195, and itself. 3BNC117 IgG also had RC1 binding competition from PGT128, SF12, and 8ANC195 Fabs. Serum from the 8 immunized macaques collected after each immunization did not display RC1-binding competition with 3BNC117.
Escolano2021
(antibody interactions, vaccine antigen design)
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3BNC117: HIV-1 bnAbs require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations. Probable mutations occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. The paper introduced the ARMADiLLO program, which estimates how probable a particular mAb mutation is, and thus the key improbable mutations were defined for a panel of 26 bnAbs. The number of improbable mutations ranged from 7 (PGT128) to 23 (VRC01 and 35O22); 3BNC117 had 16 improbable mutations out of 68 total AA mutations, and 8 indels. Single-amino acid reversion mutants were made for key improbable mutations of 3 bnAbs (CH235, VRC01, and BF520.1), and these mutant mAbs were tested for their neutralization ability. The study also noted that bnAbs that had relatively small numbers of improbable single somatic mutations had other unusual characteristics that were due to additional improbable events, such as indels (PGT128) or extraordinary CDR H3 lengths (VRC26.25).
Wiehe2018
(neutralization)
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3BNC117: The study assessed the breadths and potencies of 14 bnAbs against 36 viruses reactivated from peripheral blood CD4+ T cells from ARV-treated HIV-infected individuals by using paired neutralization and infected cell binding assays. Infected cell binding correlated with virus neutralization for 10 of 14 antibodies (VRC01, VRC07-523, 3BNC117, N6, PGT121, 10-1074, PGDM1400, PG9, 10E8, and 10E8v4-V5R-100cF). For example, the correlation for 3BNC117 had r=0.82 and P<0.0001. Heterogeneity was observed, however, with a lack of significant correlation for 2G12, CAP256.VRC26.25, 2F5, and 4E10. The study also performed paired infected cell binding and ADCC assays by using two reservoir virus isolates in combination with 9 bNAbs, and the results were consistent with previous studies indicating that infected cell binding is moderately predictive of ADCC activity for bNAbs with matched Fc domains. These data provide guidance on the selection of antibodies for clinical trials.
Ren2018
(effector function, neutralization, binding affinity, HIV reservoir/latency/provirus)
-
3BNC117: A panel of 33 CRF02_AG pseudoviruses was generated from HIV-1-infected individuals during early stages of infection. Samples represented a 15-year period 1997-2012. These viruses were best neutralized by the CD4bs-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the MPER-directed bnAb 10E8 in terms of both potency and breadth. There was a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Neutralization by 8ANC195 was also assayed. Combinations of antibodies were predicted by the CombiNaber tool to achieve full coverage across this subtype. There was increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the timespan sampled.
Stefic2019
(neutralization, acute/early infection, subtype comparisons)
-
3BNC117: 14/17 cloned mAbs from mice, immunized with either modified native-like soluble Env trimer immunogen RC1 or RC1-4fill, and 32/38 cloned mAbs from macaques, immunized once with RC1-4fill multimerized on virus-like particles bound to the desired V3-glycan patch with diverse binding mechanisms. Germline usage and CDR sequence and length were identified for all 55 mAbs but only those with published functional characterization were included in this database. In macaques, these non-neutralizing mAbs had sequence and structural similarities to inferred germline precursors of bnAbs that target V3-glycan patch including longer light chain CDRs, CDRL3 QXXDSS & SYAG motifs, and CDRL1 NIG-like motifs. Compared to parental immunogen 11MUTB, both RC1 and RC1-4fill have N156 glycan deletion to facilitate V3-glycan patch binding while RC1-4fill also has glycans added at N230, N241, N289 and N344 to mask BG505-specific glycan hole. 3BNC117 efficiently bound RC1, deglycosylated RC1 mutants, RC1-GAIA mutant, 11MUTB, 11MUTBΔ301, 10MUT and BG505.
Escolano2019
(glycosylation)
-
3BNC117: The authors review Fc effector functions, which cooperatively with Fab neutralization functions, could be used passively as immunotherapeutic or immunoprophylactic agents of HIV reservoir control or even infection prevention. One effector function, antibody-dependent complement-mediated lysis (ADCML), is seen with IgG1 and IgG3 anti-V1/V2 glycan bnAbs, PG9, PG16, PGT145; but not with 2F5, 4E10, 2G12, VRC01 and 3BNC117 unless they are delivered with anti-regulators of complement activation (RCA) antibodies. Another effector function, antibody-dependent cellular cytotoxicity (ADCC) can slow disease progression by NK-mediated degranulation of infected cells that are coated by bnAbs whose Fc region is recognized by the low affinity NK receptor, FcγRIIIA (or CD16). Strong ADCC was induced by NIH45-46, 3BNC117, 10-1074, PGT121 and 10E8, with intermediate activity for PG16 and VRC01, but no ADCC activation for 12A12, 8ANC195 and 4E10. A final effector function, antibody-dependent phagocytosis (ADP) also eliminates infected cells but through phagocytosis mediated by Fc portions of coating anti-HIV antibodies interacting with other FcγR (or FcαR) on the surface of granulocytes, monocytes or macrophages. This protective mode is less well studied but bnAbs like VRC01 have been engineered to increase phagocytosis by neutrophils. Protein engineering of bispecifics against the surface of infected or reservoir virus cells has potential in the future.
Danesh2020
(antibody interactions, assay or method development, complement, effector function, immunoprophylaxis, neutralization, immunotherapy, early treatment, review, broad neutralizer, HIV reservoir/latency/provirus)
-
3BNC117: To understand early bnAb responses, 51 HIV-1 clade C infected infants were assayed for neutralization of a 12-virus multi-clade panel. Plasma bnAbs targeting V2-apex on Env were predominant in infant elite and broad neutralizers. In infant elite neutralizers, multi-variant infection was associated with plasma bnAbs targeting diverse autologous viruses. A panel of mAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, 10-1074, BG18, AIIMS-P01, PGT121, PGT128, PGT135, VRC01, N6, 3BNC117, PGT151, 35O22, 10E8, 4E10, F105, 17b, A32, 48d, b6, 447-52d) was assayed for their ability to neutralize Env clones from infant elite neutralizers; circulating viral variants in infant elite neutralizers were most susceptible to V2-apex bnAbs.
Mishra2020a
(neutralization, polyclonal antibodies)
-
3BNC117: In vertically-infected infant AIIMS731, a rare HIV-1 mutation in hypervariable loop 2 (L184F) was studied. In patient sequences, this mutation was present in the majority of clones. A panel of 6 V2 bnAbs (PG9, PG16, PGT145, PGDM1400, CAP256.25, and CH01) was assayed for neutralization of 6 patient viral clones. The AIIMS731 viral variants segregated into 4 neutralization-sensitive and 2 resistant clones; sensitive clones carried 184F, while resistant clones carried the rare 184L mutation. A large panel of bnAbs targeting non-V2 epitopes was used to assess the neutralization of the 6 patient viral variants. The bnAb panel consisted of V3/N332 glycan supersite bnAbs (10-1074, BG18, AIIMS-P01, PGT121, PGT128, and PGT135), CD4bs bnAbs (VRC01, VRC03, VRC07-523LS, N6, 3BNC117, and NIH45-46 G54W), a silent face-targeting bnAb (PG05), fusion peptide and gp120-gp41 interface bnAbs (PGT151, 35O22, and N123-VRC34.01), and MPER bnAbs (10E8, 4E10, and 2F5). All of these bnAbs had similar neutralization efficiencies for all 6 clones, suggesting that the L184F mutation was specific for viral escape from neutralization by V2 apex bnAbs. A panel of non-neutralizing mAbs (V3 loop-targeting non-nAbs 447-52D and 19b, and CD4-induced non-nAbs 17b, A32, 48d, and b6), were also assessed; 2 of the variants (the same 2 susceptible to the V2 bnAbs) showed moderate neutralization by 447-52D, 19b, 17b, and 48d. The structure of ligand-free BG505 SOSIP trimer revealed that the side chain of L184 was outward facing and did not make significant intraprotomeric interactions, but upon mutating L184 to F184, a disruption of the accessible surface between the bulky side chain of F184 on one protomer and R165 on the neighboring protomer was seen. Thus, the L184F mutation resulted in increased susceptibility to neutralization by antibodies known to target the relatively more open conformation of Env on tier 1 viruses, suggesting that the rare L184F mutation allowed Env to sample more open states resembling the CD4-bound conformation where the CCR5 binding site is exposed.
Mishra2020
(neutralization, polyclonal antibodies)
-
3BNC117: This report characterizes an additional antiviral activity of some bnAbs to block HIV-1 release by tethering viral particles at the surface of infected cells in vitro in a bivalency-dependent manner. After cultivation of infected primary CD4+ T cells with individual bnAbs, supernatant p24 levels were negatively correlated with cell-associated Gag levels, Env binding and neutralization potency while cell-associated Gag levels and Env binding positively correlated with each other and individually with neutralization potency. The capacity to mediate this tethering activity varied among different classes of mAbs: none of the 3 non-neutralizing mAbs, 1/5 bnAbs targeting the MPER or gp120/gp41 interface and all 9 of the bnAbs targeting the V3 and V1/V1 loops or the CD4bs demonstrated this activity against at least 1/3 diverse viral strains (AD8, CH058 and vKB18). Five of these latter 9 bnAbs displayed tethering activity against all 3 strains. Surface aggregation of mature virions and bnAb 10-1074 was observed in CH058-infected primary CD4+ T cells and CHME macrophage-like cells. CD4bs-targeting bnAb 3BNC117 displayed tethering activity against all 3 strains.
Dufloo2022
(binding affinity)
-
3BNC117: This paper reports the safe and relatively well-tolerated coadministration, shortly after ART initiation, of the CD4bs-targeting bnAb 3BNC117 and the latency-reversing agent romidepsin in HIV-1-infected adults, as part of a phase 1b/2a therapeutic clinical trial (NCT03690193). Early treatment with 3BNC117 increased the elimination of plasma viruses and infected central memory CD4+ T cells, enhanced durable Gag-specific CTL-mediated immunity, and was associated with sustained virologic control during a 12-week analytical treatment intervention among persons with 3BNC117-sensitive viruses.
Gunst2022
(immunotherapy, HAART, ART, supervised treatment interruptions (STI), HIV reservoir/latency/provirus)
-
3BNC117: This is the first report of a therapeutic clinical trial (phase 2A) in HIV-1-infected humans of the combination of the potent bnAb 3BNC117 and the latency-reversing agent romidepsin. While generally safe and well tolerated, this combination did not substantially affect the HIV-1 reservoir or delay viral rebound. The median time to viral rebound during an analytic treatment interruption was 18 days and 28 days, respectively, for 10 subjects who received 3BNC117 and romidepsin and 7 subjects who received only romidepsin but this difference was not clinically meaningful.
Gruell2022
(immunotherapy, supervised treatment interruptions (STI), broad neutralizer, HIV reservoir/latency/provirus)
-
3BNC117: This is a report of a phase 1b therapeutic clinical trial in which humans chronically infected with HIV-1 received 7 doses of a combination of two bnAbs (3BNC117 and 10-1074), in the presence or absence of ART, which were generally safe and well-tolerated. 76% (13/17) of subjects who discontinued ART 2 days after first bnAb infusion maintained virologic suppression for at least 20 weeks. There was a moderate but significant reduction in the absolute number and relative representation of intact proviruses in the subjects treated with 3BNC117 and 10-1074 that was not seen in a parallel cohort of HIV-1-infected subjects who only received ART without bnAb therapy. The average serum half-life of 3BNC117 was 14.9 days. The average serum concentration of 3BNC117 at the time of rebound in individuals who remained suppressed after week 20 was 3.5 μg/ml. Rebound generally occurred only after 3BNC117 serum concentration dropped below 10 μg/ml.
Gaebler2022
(antibody interactions, immunotherapy, HAART, ART, supervised treatment interruptions (STI), broad neutralizer, chronic infection, HIV reservoir/latency/provirus)
-
3BNC117: This paper isolated and characterized V3-glycan bNAb Ab1485 produced by an elite neutralizing SHIVAD8-EO-infected macaque identified as CE8J. For comparison with Ab1485, the binding of gp120 CD4bs mAb 3BNC117 to BG505 was nearly completely inhibited by itself and partially inhibited by gp41-gp120 interface mAb 8ANC117. MAbs 10-1074, PG9 and VRC34, which all targeted other regions of Env, did not inhibit binding.
Wang2020
(antibody interactions)
-
3BNC117: This study inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation, including a phylogeny of 45 naturally-paired mAbs from donor NIH45. Nine new lineage members were isolated from donor NIH45, named DH651.1 - DH561.9. The study also derived VH and VL reverted forms of several VRC01-class mAbs derived from other donors (12A12, 3BNC60, 3BNC117, VRC20, VRC23, and VRC18b). Early mutations within the VRC01 lineage defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B-cell maturation toward the development of neutralization breadth. VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan. An X-ray structure and molecular dynamics simulation of VRC08 were studied to elucidate this process.
Bonsignori2018
(neutralization, antibody lineage)
-
3BNC117: To improve the potency and breadth of bNabs, structure-based design methods were used to generate engineered variants of 6 VRC01-class mAbs (VRC01, VRC07-523LS, VRC08, N6, 3BNC117 and N49P7). Several of the engineered variant mAbs had improved potency, breadth, and pharmacokinetics. The specific mutations introduced, singly or in combination, included mutation of heavy chain (HC) amino acid 54, replacement of the native HC FR3 with FR3 from VRC03 (03FR3), introduction of the "LS" HC mutations (M428L and N434S in the Fc region), and light chain (LC) truncation of the first 2 or 3 residues. In previous studies, the LS mutation has been shown to improve antibody half-life without significantly affecting potency, while alteration of LC residues 1, 2, and 3 can improve the potency of some mAbs. LC mutations decreased potency and breadth of 3BNC117. Variants of 3BNC117 were produced with HC mutations T54W + 03FR3, with and without deletion of the first 2 or 3 residues of the LC. These variants had the same or poorer mean potency than the parental 3BNC117 and were not selected for further study.
Kwon2021
(neutralization, structure, broad neutralizer)
-
3BNC117: IgA and IgG bNAbs of 3 distinct B cell lineages were characterized in a viremic controller (pt7). Two lineages comprised only IgG+ or IgA+ blood memory B cells; the third combined both IgG and IgA clonal variants. BNAb 7-269 in the IgA-only lineage displayed the highest neutralizing capacity despite limited somatic mutation. Immunotherapy with 7-269 in humanized mice delayed viral rebound. AD8-infected cell killing by primary human NK cells via ADCC was observed with all pt7 bNAbs binding strongly to target cells and expressed as IgGs, except for 7-155. Broadly nAbs in all three lineages targeted the N332 glycan supersite. Epitope mapping showed that all pt7 IgA and IgG bNAbs target the high-mannose patch centered on the N332 glycan without interacting with the V3 loop base, which contrasts with numerous bNAbs targeting the N332 supersite. The cryo-EM structure of 7-269 in complex with BG505 SOSIP revealed an epitope mainly composed of sugar residues comprising the N332 and N295 glycans; onto which 7-269 positions itself in a structurally similar way to 2G12. Binding and cryo-EM structural analyses showed that antibodies from the two other lineages interact mostly with glycans N332 and N386. Hence, multiple B cell lineages of IgG and IgA bNAbs focused on a unique HIV-1 site of vulnerability can codevelop in HIV-1 viremic controllers. Other antibodies used as controls included 10-188, 3BNC117, PGT121, PGT135, 10-1074, BG8, BG18, and SF12.
Lorin2022
(antibody binding site, binding affinity, structure)
-
3BNC117: This review focuses on the potential for bNAbs to induce HIV-1 remission, either alone or in combination with latency reversing agents, therapeutic vaccines, or other novel therapeutics. Ongoing human trials aimed at HIV therapy or remission are utilizing the following antibodies, alone or in combination: VRC01, VRC01-LS, VRC07-523-LS, 3BNC117, 10-1074, 10-1074-LS, PGT121, PGDM1400, 10E8.4-iMab, and SAR441236 (trispecific VRC01/PGDM1400-10E8v4). Ongoing non-human primate studies aimed to target, control, or potentially eliminate the viral reservoir are utilizing the following antibodies, alone or in combination: 3BNC117, 10-1074, N6-LS, PGT121, and the GS9721 variant of PGT121.
Hsu2021
(antibody interactions, immunotherapy, review, HIV reservoir/latency/provirus)
-
3BNC117: A series of mutants was produced in the CAP256-VRC26.25 heavy chain for the purpose of avoiding the previously-identified proteolytic cleavage at position K100m. Neutralization of the mutants was tested, and the cleavage-resistant variant that showed the greatest potency was K100mA. In addition to the K100mA mutation, an LS mutation was added to the Fc portion of the heavy chain, as this change has been shown to improve the half-life of antibodies used for passive administration without affecting neutralization potency. The resulting construct was named CAP256V2LS. The pharmacokinetics of CAP256V2LS were assessed in macaques and mice, and it showed a profile similar to other antibodies used for immunotherapy. The antibody lacked autoreactivity. Structural analysis of wild-type CAP256-VRC26.25 showed that the K100m residue is not involved in interaction with the Env trimer. Neutralization data for 3BNC117 were used for comparison purposes.
Zhang2022
(neutralization, immunotherapy, broad neutralizer)
-
3BNC117: An ART-naive HIV-controlling patient SA003 was found to have a high level of serum bNAb activity, and broadly neutralizing mAb LN01 IgG3 was isolated from patient serum. MAb 3BNC117 was used as a comparison in an assay of ADCC.
Pinto2019
(effector function)
-
3BNC117: In 8 ART-treated patients, latent viruses were induced by a viral outgrowth assay and assayed for their sensitivity to neutralization by 8 broadly neutralizing antibodies (VRC01, VRC07-523, 3BNC117, PGT121, 10-1074, PGDM1400, VRC26.25, 10E8v4-V5F-100cF). The patients' inducible reservoir of autologous viruses was generally refractory to neutralization and higher Env diversity correlated with greater resistance to neutralization.
Wilson2021
(autologous responses, neutralization, HAART, ART, HIV reservoir/latency/provirus)
-
3BNC117: In this clinical trial, administration of PGT121 was well tolerated in both HIV-uninfected and HIV-infected individuals. PGT121 potently and transiently inhibited HIV-1 replication in viremic individuals who had PGT121-sensitive viruses at enrollment. There were several distinct viral evolutionary patterns associated with the emergence of PGT121 resistance and viral rebound. These pathways included single point mutations, multiple point mutations, and viral recombination that led to increased resistance. Loss of D325 and the glycan at N332 were specifically associated with resistance in multiple patients. In some patients, resistance to PGT121 was accompanied by resistance to other bNAbs (10-1074, PGDM1400, or 3BNC117), as measured by neutralization assays.
Stephenson2021
(glycosylation, mutation acquisition, neutralization, immunotherapy)
-
3BNC117: Extensive structural and biochemical analyses demonstrated that PGT145 achieves recognition and neutralization by targeting quaternary structure of the cationic trimer apex with long and unusually stabilized anionic β-hairpin HCDR3 loops. Analysis of generated cyroEM structure of BG505 SOSIP.664-3BNC117 (resolution of ˜4.4A) revealed that residues in 3BNC117 HFR3 interact favorably with binding site elements including H71a with N197 glycan and W71d with Env 308 (32%R & 39%H) on the adjacent gp120 protomer. Comparison with generated cryoEM structure of BG505 SOSIP.664-3BNC117-PGT145 (resolution of ˜4.3A) revealed that 3BNC117-binding induced subtle increase in spacing between N160 glycan triad which would provide greater apical site access for PGT145.
Lee2017
(antibody binding site, structure)
-
3BNC117: Humanized mice were grafted with CD34+ T cells isolated from human umbilical cords and later challenged by intra-rectal infection with HIV-1 strain NL4-3. Mice treated with a mix of 3 bNAbs (10-1074, 3BNC117, and SF12) resisted mucosal infection.
Vanshylla2021
(neutralization, immunotherapy)
-
3BNC117: Novel Env pseudoviruses were derived from 22 patients in China infected with subtype CRF01_AE viruses. Neutralization IC50 was determined for 11 bNAbs: VRC01, NIH45-46G54W, 3BNC117, PG9, PG16, 2G12, PGT121, 10-1074, 2F5, 4E10, and 10E8. The CRF01_AE pseudoviruses exhibited different susceptibility to these bNAbs. Overall, 4E10, 10E8, and 3BNC117 neutralized all 22 env-pseudotyped viruses, followed by NIH45-46G54W and VRC01, which neutralized more than 90% of the viruses. 2F5, PG9, and PG16 showed only moderate breadth, while the other three bNAbs neutralized none of these pseudoviruses. Specifically, 10E8, NIH45-46G54Wand 3BNC117 showed the highest efficiency, combining neutralization potency and breadth. Mutations at position 160, 169, 171 were associated with resistance to PG9 and PG16, while loss of a potential glycan at position 332 conferred insensitivity to V3-glycan-targeting bNAbs. These results may help in choosing bNAbs that can be used preferentially for prophylactic or therapeutic approaches in China.
Wang2018a
(assay or method development, neutralization, subtype comparisons)
-
3BNC117: A novel CD4bs bnAb, 1-18, is identified with breadth (97% against a 119-strain multiclade panel) and potency (IC50 = 0.048 µg/mL) exceeding most VH1-46 and VH1-2 class bnAbs like 3BNC117, VRC01, N6, 8ANC131, 10-1074, PGT151, PGT121, 8ANC195, PG16 and PGDM1400. 1-18 effectively restricts viral escape better than bnAbs 3BNC117 and VRC01. As with VRC01-like Abs, 1-18 targets the CD4bs but it recognizes the epitope differently. Neutralizing activity against VRC01 Ab-class' escape mutants is maintained by 1-18. In humanized mice infected by strain HIV-HIV-1YU2, viral suppression is also maintained by 1-18. VH1-46-derived B cell clone 4.1 from patient IDC561 produced potent, broadly active mAbs. Subclone 4.1 is characterized by a 6 AA CDRH1 insertion lengthening it from 8 to 14 AA and produces bNAbs 1-18 and 1-55. Cryo-EM at 2.5A of 1-18 in complex with BG505SOSIP664 suggests their insertion increases inter-protomer contacts by a negatively charged DDDPYTDDD motif, resulting in an enlargement of the buried surface on HIV-1 gp120. Variation in glycosylation is thought to confer higher neutralizing activity on 1-18 over 1-55.
Schommers2020
(neutralization)
-
3BNC117: Soluble versions of HIV-1 Env trimers (sgp140 SOSIP.664) stabilized by a gp120-gp41 disulfide bond and a change (I559P) in gp41 have been structurally characterized. Cross-linking/mass spectrometry to evaluate the conformations of functional membrane Env and sgp140 SOSIP.664 has been reported. Differences were detected in the gp120 trimer association domain and C terminus and in the gp41 HR1 region which can guide the improvement of Env glycoprotein preparations and potentially increase their effectiveness as a vaccine.
Castillo-Menendez2019
(vaccine antigen design, structure)
-
3BNC117: This study reported analytical challenges associated with the formulation of 3BNC117 and PGT121 and the mixture of these mAbs. The single and mixture formulations were characterized for relative solubility and conformational stability at multiple temperatures, followed by stability and neutralization studies. Specific concentration-dependent aggregation rates at 30°C and 40°C were measured by size exclusion chromatography for the individual bnAbs with the mixture showing intermediate behavior. Interestingly, although the relative ratio of the 2 bnAbs remained constant at 4°C, the ratio of 3BNC117 to PGT121 increased in the dimer that formed during storage at 40°C.
Patel2018
(antibody interactions, neutralization)
-
3BNC117: In an attempt to engage appropriate germline B cells that give rise to bNAbs, a combination of Env glycan modifications that permit far greater neutralization potency by near germline forms of multiple VRC01-class bNAbs were tested. The authors assessed CD4bs bNAbs for neutralizing activity against of Env-pseudotyped viruses (EPV) that were either Man5-enriched and/or had targeted glycan deletion and concluded that neutralization by germline-reverted forms of VRC01-class bNAbs requires a combination of both Man5-enrichment and glycan deletion. In particular, Man5-enrichment increased the sensitivity of 426c by 8–12 fold when assayed with mature VRC01, 3BNC117, VRC-CH31 and CH103, and this sensitivity increased further by targeted glycan deletion. Furthermore, Man5-enrichment increased the sensitivity of subtype C transmitted-founder 426c EPV that lacked glycan N276, and those that lacked two glycans at N460 and N463, to mature VRC01 by ˜10-fold.
LaBranche2018
(antibody interactions, antibody lineage)
-
3BNC117: A dose-escalation phase 1b study in HIV-1-infected individuals to evaluate the safety, pharmacokinetics and antiretroviral activity of the combination of the Abs 3BNC117 and 10–1074 has been reported. Participants in groups 1A and 1B were virologically suppressed on ART and were randomized in a 2:1 ratio to receive one intravenous infusion of each of 3BNC117 and 10–1074 or placebo. Viremic individuals off ART were enrolled in group 1C or group 3, and received one intravenous infusion (group 1C) or three intravenous infusions (group 3, every two weeks) of each 3BNC117 and 10–1074. The combination of 3BNC117 and 10–1074 was more effective in suppressing viremia than either antibody alone. However, 3BNC117 and 10–1074 infusions failed to suppress viremia to undetectable levels in the two dual antibody-sensitive individuals with the highest pre-infusion viral load despite persistent reductions for up to 12 weeks.
Bar-On2018
(neutralization, immunotherapy, HAART, ART)
-
3BNC117: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. The G458Y signature mutation conferred complete resistance (IC50> 25 mg/mL) to 3BNC117 and can neutralize the CH505 TF (IC50 0.03 mg/mL). 3BNC117 has reduced breadth and potency against C clade viruses.
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, subtype comparisons, broad neutralizer)
-
3BNC117: Three vaccine regimens administered in guinea pigs over 200 weeks were compared for ability to elicit NAb polyclonal sera. While tier 1 NAb responses did increase with vaccination, tier 2 NAb heterologous responses did not. The 3 regimens were C97 (monovalent, Clade C gp140), 4C (tetravalent, 4 Clade C mosaic gp140s), ABCM (tetravalent, Clades A, B, C and mosaic gp140s). Polyclonal sera generated from all 3 regimens were able to outcompete 3BNC117 binding to C97 gp140, suggesting that the sera contains antibodies that bind in the vicinity of CD4bs.
Bricault2018
(antibody generation, vaccine-induced immune responses, polyclonal antibodies)
-
3BNC117: In this phase 1b clinical trial, combination therapy with 3BNC117 and 10-1074 maintained suppression for between 15 and more than 30 weeks (median of 21 weeks) in nine out of 11 enrolled HIV-1 infected individuals. Subjects had been on ART until administration of combination therapy. None of the rebound viruses from pre-infusion latent reservoirs were resistant to both antibodies. Most were resistant to 10-1074 but still sensitive to 3BNC117.
Mendoza2018
(immunotherapy)
-
3BNC117: In vitro neutralization data against 25 subtype A, 100 C, and 20 D pseudoviruses of 8 bNAbs (3BNC117, N6, VRC01, VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10–1074, PGT121) and 2 bispecific Abs under clinical development (10E8-iMAb, 3BNC117-PGT135) was studied to assess the antibodies’ potential to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. In vivo protection of these Abs and their 2-Ab combination was predicted using a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Conclusions were that 1. bNAb combinations outperform individual bNAbs 2. Different bNAb combinations were optimal against different HIV subtypes 3. Bispecific 10E8-iMAb outperformed all combinations, and 4. 10E8-iMAb in combination with other conventional Abs was predicted to be the best combination against HIV-infection. 3BNC117 + CAP256-VRC26.25 was the most potent combination against subtype D.
Wagh2018
(neutralization, computational prediction, immunotherapy)
-
3BNC117: A simple method to quantify and compare serum neutralization probabilities in described. The method uses logistic regression to model the probability that a serum neutralizes a virus with an ID50 titer above a cutoff. The neutralization potency (NP) identifies where the probabilities of neutralizing and not neutralizing a virus are equal and is not absolute as it depends on the ID50 cutoff. It provides a continuous measure for sera, which builds upon established tier categories now used to rate virus sensitivity. These potency comparisons are similar to comparing geometric mean neutralization titers, but instead are represented in tier-like terms. Increasing the number of bNAbs increases NP and slope, where the higher the slope, the sharper the boundary (lower scatter) between viruses neutralized and not neutralized. 3BNC117 was used in analysis of monoclonal bNAb combinations.
Hraber2018
(assay or method development, neutralization)
-
3BNC117: This review summarizes current advances in antibody lineage-based design and epitope-based vaccine design. Antibody lineage-based design is described for VRC01, PGT121 and PG9 antibody classes, and epitope-based vaccine design is described for the CD4-binding site, as well as fusion peptide and glycan-V3 cites of vulnerability.
Kwong2018
(antibody binding site, vaccine antigen design, vaccine-induced immune responses, review, antibody lineage, broad neutralizer, junction or fusion peptide)
-
3BNC117: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. 3BNC117 was isolated from human B cell clones and is functionally similar to VRC01. Both 3BNC117 and 3BNC117-LS are in Phase I clinical trials (Table 2). Antigenic region CD4 binding site (Table:1).
Walker2018
(antibody binding site, review, broad neutralizer)
-
3BNC117: Polyreactive properties of natural and artificially engineered HIV-1 bNAbs were studied, with almost 60% of the tested HIV-1 bNAbs (including this one) exhibiting low to high polyreactivity in different immunoassays. A previously unappreciated polyreactive binding for PGT121, PGT128, NIH45-46W, m2, and m7 was reported. Binding affinity, thermodynamic, and molecular dynamics analyses revealed that the co-emergence of enhanced neutralizing capacities and polyreactivity was due to an intrinsic conformational flexibility of the antigen-binding sites of bNAbs, allowing a better accommodation of divergent HIV-1 Env variants.
Prigent2018
(antibody polyreactivity)
-
3BNC117: A panel of bnAbs were studied to assess ongoing adaptation of the HIV-1 species to the humoral immunity of the human population. Resistance to neutralization is increasing over time, but concerns only the external glycoprotein gp120, not the MPER, suggesting a high selective pressure on gp120. Almost all the identified major neutralization epitopes of gp120 are affected by this antigenic drift, suggesting that gp120 as a whole has progressively evolved in less than 3 decades.
Bouvin-Pley2014
(neutralization)
-
3BNC117: The first cryo-EM structure of a cross-linked vaccine antigen was solved. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a bNAb PGV04 Fab fragment revealed how cross-linking affects key properties of the trimer. SOSIP and GLA-SOSIP trimers were compared for antigenicity by ELISA, using a large panel of mAbs previously determined to react with BG505 Env. Non-NAbs globally lost reactivity (7-fold median loss of binding), likely because of covalent stabilization of the cross-linked ‘closed’ form of the GLA-SOSIP trimer that binds non-NAbs weakly or not at all. V3-specific non-NAbs showed 2.1–3.3-fold reduced binding. Three autologous rabbit monoclonal NAbs to the N241/N289 ‘glycan-hole’ surface, showed a median ˜1.5-fold reduction in binding. V3 non-NAb 4025 showed residual binding to the GLA-SOSIP trimer. By contrast, bNAbs like 3BNC117 broadly retained reactivity significantly better than non-NAbs, with exception of PGT145 (3.3-5.3 fold loss of binding in ELISA and SPR).
Schiffner2018
(binding affinity, structure)
-
3BNC117: M428L and N434S mutations [referred to as “LS”] were introduced into the genes encoding the crystallizable fragment domains of 3BNC117 and 10-1074 bNAbs to increase their half-lives. The efficacy of modified bNAbs in blocking infections following repeated low dose mucosal challenges of rhesus macaques with the Tier 2 SHIVAD8-EO was evaluated. The most striking result was the long period of protective efficacy conferred by a single injection of crystallizable fragment domain-modified hbNAbs in macaques compared to that previously reported. A single intravenous infusion of the 10-1074-LS bNAb protected a cohort of 6 monkeys for up to 8.5 months (18 to 37 weeks). LS mutation in 10-1074 lengthened the median time until SHIVAD8-EO acquisition from 12.5 to 27 weeks, with 10-1074-LS bNAb measurable in the serum for 26 to 41 weeks and a calculated half-life of 3.8 weeks. The effects of the LS change on 3BNC117 were more modest than 10-1074, with a shorter half-life (2.6 versus 3.8 weeks), smaller increase in half-life (2 vs. 3.8-fold), and lower initial serum concentrations.
Gautam2018
(immunoprophylaxis)
-
3BNC117: Panels of C clade pseudoviruses were computationally downselected from the panel of 200 C clade viruses defined by Rademeyer et al. 2016. A 12-virus panel was defined for the purpose of screening sera from vaccinees. Panels of 50 and 100 viruses were defined as smaller sets for use in testing magnitude and breadth against C clade. Published neutralization data for 16 mAbs was taken from CATNAP for the computational selections: 10-1074, 10-1074V, PGT121, PGT128, VRC26.25, VRC26.08, PGDM1400, PG9, PGT145, VRC07-523, 10E8, VRC13, 3BNC117, VRC07, VRC01, 4E10.
Hraber2017
(assay or method development, neutralization)
-
3BNC117: Early administration of bNAbs in a macaque-SHIV model is associated with a persistent very low level of viremia resulting in long-term infection control. Passive combination immunotherapy of 3BNC117 and 10-1074, 3 days after intrarectal infection, and targeting non-overlapping epitopes on the Env spike effected viremic suppression for 56-177 days, with rebound directly correlated to plasma concentration of bNAb. On day 56 macaque MVJ experienced SHIVAD8-EO rebound when plasma 3BNC117 decayed below 1 µg/ml.
Nishimura2017
(acute/early infection, immunotherapy)
-
3BNC117: The next generation of a computational neutralization fingerprinting (NFP) being used as a way to predict polyclonal Ab responses to HIV infection is presented. A new panel of 20 pseudoviruses, termed f61, was developed to aid in the assessment of experimental neutralization. This panel was used to assess 22 well-characterized bNAbs and mixtures thereof (HJ16, VRC01, 8ANC195, IGg1b12, PGT121, PGT128, PGT135, PG9, PGT151, 35O22, 10E8, 2F5, 4E10, VRC27, VRC-CH31, VRC-PG20, PG04, VRC23, 12A12, 3BNC117, PGT145, CH01). The new algorithms accurately predicted VRC01-like and PG9-like antibody specificities.
Doria-Rose2017
(neutralization, computational prediction)
-
3BNC117: This review focuses on the potential role of HIV-1-specific NAbs in preventing HIV-1 infection. Several NAbs have provided protection from infection in SHIV challenge studies in primates: b12, VRC01, VRC07-523LS, 3BNC117, PG9, PGT121, PGT126, 10-1074, 2G12, 4E10, 2F5, 10E8.
Pegu2017
(immunoprophylaxis, review)
-
3BNC117: In 33 individuals (14 uninfected and 19 HIV-1-infected), intravenous infusion of 10-1074 was well tolerated. In infected individuals with sensitive strains, 10-1074 decreased viremia, but escape variants and viral rebound occurred within a few weeks. Escape variants were also resistant to V3 antibody PGT121, but remained sensitive to antibodies targeting other epitopes (3BNC117, VRC01 or PGDM1400). Loss of the PNGS at position N332 or 324G(D/N)IR327 mutation was associated with resistance to 10-1074 and PGT121.
Caskey2017
(immunotherapy)
-
3BNC117: This study investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit NAbs. Rabbits were immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). N197 glycan- and residue 230- removal conferred sensitivity to Trimer VLP sera and DNA trimer sera respectively, showing for the first time that strain-specific holes in the "glycan fence" can allow the development of tier 2 NAbs to native spikes. All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. VRC01 was 1 of 4 reference VRC01-like bNAbs - VRC01, 3BNC117, 8ANC131, CH103.
Crooks2015
(glycosylation, neutralization)
-
3BNC117: Infusions of 3BNC117 were given to 13 HIV-infected individuals during analytical treatment interruption. The antibody was well tolerated. Infusions were associated with a delay in viral rebound. In most individuals, rebound viruses showed increased resistance to 3BNC117, but in 30% of patients the virus showed no sign of escape over a period of 9-19 weeks.
Scheid2016
(escape, immunotherapy)
-
3BNC117: Chimeric antigen receptors, i.e., fusion proteins made from single-chain antibodies, may be a useful approach to immunotherapy. A set of mAbs were chosen based on their binding to a variety of sites on Env and availability of antibody sequences. The chimeric receptors were created by fusing the antibody's heavy chain, light chain, and two signaling domains into a single molecule. All 7 antibodies used to make the chimeric receptors (10E8, 3BNC117, PGT126, VRC01, X5, PGT128, PG9) showed specific killing of HIV-1 infected cells and suppression of viral replication against a panel of HIV-1 strains.
Ali2016
(immunotherapy, chimeric antibody)
-
3BNC117: This review classified and mapped the binding regions of 32 bNAbs isolated 2010-2016.
Wu2016
(review)
-
3BNC117: In neutralization assays of antibody mixtures, there was a modest synergy between the CD4bs VRC01 and either of the two CD4i MAbs E51 and 412d. The synergy is likely the result of the ability of CD4i antibodies (E51 or 412d) to induce the open state and facilitate access to the CD4 binding site. The presence of E51 enhanced the Env binding of VRC01, NIH45-46, NIH45-46G54W, and to a lesser extent 3BNC117.
Gardner2016
(antibody interactions)
-
3BNC117: This study assessed the ADCC activity of antibodies of varied binding types, including CD4bs (b6, b12, VRC01, PGV04, 3BNC117), V2 (PG9, PG16), V3 (PGT126, PGT121, 10-1074), oligomannose (2G12), MPER (2F5, 4E10, 10E8), CD4i (17b, X5), C1/C5 (A32, C11), cluster I (240D, F240), and cluster II (98-6, 126-7). ADCC activity was correlated with binding to Env on the surfaces of virus-infected cells. ADCC was correlated with neutralization, but not always for lab-adapted viruses such as HIV-1 NLA-3.
vonBredow2016
(effector function)
-
3BNC117: This review summarizes representative anti-HIV MAbs of the first generation (2G12, b12, 2F5, 4E10) and second generation (PG9, PG16, PGT145, VRC26.09, PGDM1400, PGT121, PGT124, PGT128, PGT135, 10-1074, VRC01, 3BNC117, CH103, PGT151, 35O22, 8ANC195, 10E8). Structures, epitopes, VDJ usage, CDR usage, and degree of somatic hypermutation are compared among these antibodies. The use of SOSIP trimers as immunogens to elicit B-cell responses is discussed.
Burton2016
(review, structure)
-
3BNC117: bNAbs were found to have potent activating but not inhibitory FcγR-mediated effector function that can confer protection by blocking viral entry or suppressing viremia. bNAb activity is augmented with engineered Fc domains when assessed in in vivo models of HIV-1 entry or in therapeutic models using HIV-1-infected humanized mice. Enhanced FcγR engagement is not restricted by epitope specificity or neutralization potency as chimeras composed of human anti-CD4bs 3BNC117 Fab and mouse Fc had improved or reduced in vivo activity depending on the Fc used.
Bournazos2014
(neutralization, chimeric antibody)
-
3BNC117: A comprehensive antigenic map of the cleaved trimer BG505 SOSIP.664 was made by bNAb cross-competition. Epitope clusters at the CD4bs, quaternary V1/V2 glycan, N332-oligomannose patch and new gp120-gp41 interface and their interactions were delineated. Epitope overlap, proximal steric inhibition, allosteric inhibition or reorientation of glycans were seen in Ab cross-competition. Thus bNAb binding to trimers can affect surfaces beyond their epitopes. Among CD4bs binding bNAbs, 3BNC117 recognizes trimer similarly to CH103, CH106, 1NC9 and VRC01, and is inhibited by sCD4. It enhanced binding of several V1/V2-glycan, V3-glycan or outer domain (OD)-glycan bNAbs; and 3BNC117 binding is enhanced by Ab 8ANC195. OD-glycan bNAbs, PGT135 and PGT136, though ˜ 5x less efficient binders of trimer, were able to unidirectionally inhibit binding of 3BNC117, as also other CD4bs bNAbs, VRC01, 2BNC60, NIH45-46. 3BNC117, alongwith 1NC9 differs slightly from more typical CD4bs bNAbs by its dependence on N-276 glycan.
Derking2015
(antibody interactions, neutralization, binding affinity, structure)
-
3BNC117: A new trimeric immunogen, BG505 SOSIP.664 gp140, was developed that bound and activated most known neutralizing antibodies but generally did not bind antibodies lacking neuralizing activity. This highly stable immunogen mimics the Env spike of subtype A transmitted/founder (T/F) HIV-1 strain, BG505. Anti-CD4bs bNAb 2BNC117 neutralized BG505.T332N, the pseudoviral equivalent of the immunogen BG505 SOSIP.664 gp140, and was shown to recognize and bind the immunogen too.
Sanders2013
(assay or method development, neutralization, binding affinity)
-
3BNC117: This review discusses the application of bNAbs for HIV treatment and eradication, focusing on bnAbs that target key epitopes, specifically: 2G12, 2F5, 4E10, VRC01, 3BNC117, PGT121, VRC26.08, VRC26.09, PGDM1400, and 10-1074. 3BNC117 is a CD4bs-specific bnAb that has been administered in both primate and human trials.
Stephenson2016
(immunotherapy, review)
-
3BNC117: This review discusses the breakthroughs in understanding of the biology of the transmitted virus, the structure and nature of its envelope trimer, vaccine-induced CD8 T cell control in primates, and host control of bnAb elicitation.
Haynes2016
(review)
-
3BNC117: This review summarized the novel strategies for HIV vaccine discovery. Multiple therapeutic vaccines have failed in the past, in a non placebo controlled trial, a Tat vaccine demonstrated immune cell restoration, reduction of immune activation, and reduced HIV-1 DNA viral load. bNAbs offer both prevention potential and treatment. In early-phase clinical trials, VRC01 reduced viral load in HIV-1-infected individuals not on HAART.
Gray2016
(vaccine antigen design, vaccine-induced immune responses, HAART, ART, review)
-
3BNC117: This study examined the neutralization of group N, O, and P primary isolates of HIV-1 by diverse antibodies. Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O isolates, 1 group N isolate, and the group P isolates were neutralized by PG9 and/or PG16 or PGT145 at low concentrations. None of the non-M primary isolates were neutralized by bNAbs targeting other regions, except 10E8, which weakly neutralized 2 group N isolates, and 35O22 which neutralized 1 group O isolate. Bispecific bNAbs (PG9-iMab and PG16-iMab) very efficiently neutralized all non-M isolates with IC50 below 1 ug/mL, except for 2 group O strains. Anti-CD4bs bNAb 3BNC117 was able to neutralize only 1/16 tested non-M primary isolates at an IC50< 10µg/ml, RBF208,M/O at 0.63 µg/ml.
Morgand2015
(neutralization, subtype comparisons)
-
3BNC117: The neutralization of 14 bnAbs was assayed against a global panel of 12 or 17 Env pseudoviruses. From IC50, IC80, IC90, and IC99 values, the slope of the dose-response curve was calculated. Each class of Ab had a fairly consistent slope. Neutralization breadth was strongly correlated with slope. An IIP (Instantaneous Inhibitory Potential) value was calculated, based on both the slope and IC50, and this value may be predictive of clinical efficacy. 3BNC117, a CD4bs bnAb belonged to a group with slopes >1.
Webb2015
(neutralization)
-
3BNC117: This study presented structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb–426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. It reported that unlike most antibodies, the overall final structures of VRC01 class antibodies are formed before the antibodies mature. The overall charge on 3BNC117 is +5, average for VRC01-class antibodies. It requires the A61P substitution in mature bNAb for maximal neutralization, even though it thermally destabilizes the helix in that part of 3BNC117.
Scharf2016
(structure)
-
3BNC117: The dynamics and characteristics of anti-antibody responses were described for monkeys that received adenovirus-mediated delivery of either rhesus anti-SIV antibody constructs (4L6 or 5L7) in prevention trials, or a combination of rhesusized human anti-HIV antibodies (1NC9/8ANC195/3BNC117 or 10-1074/10E8/3BNC117) in therapy trials. Anti-antibody responses to the human mAbs were correlated to the distance from the germline Ab sequences.
Martinez-Navio2016
(immunotherapy)
-
3BNC117: Based on the results of 3BNC117 administered to human subjects, mathematical modeling was unable to recapitulate the kinetics of the viral decline. Revision of the model to fit the data suggested that the antibody may clear infected cells, in addition to neutralizing free virions. In in vitro experiments, 3BNC177, PG16, and 10-1074 were able to stain cells infected with HIV-1 YU2. Both 3BNC117 and 10-1074 recognized cells infected with primary virus isolates from human subjects that had been previously infused with 3BNC117. Either 3BNC117 alone, or in combination with 10-1074, was able to accelerate the clearance of YU2-infected cells in humanized mice, decreasing the half life of the infected cell. This result was shown to be mediated by the Fc-gamma receptor.
Lu2016
(effector function, immunotherapy)
-
3BNC117: A single infusion of 3BNC117 was administered to 27 HIV-1-infected individuals. Analysis of env sequences over time revealed significant increases in sequence diversity. Improved neutralizing responses to tier-2 viruses were seen in nearly all study subjects over a 6-month period, while untreated individuals showed little change. Viremic individuals receiving 3BNC117, however, produced Abs to autologous virus that were sensitive or resistant. It is unknown how passively-administered antibodies accelerate the emergence of bnAbs, but this appears to be the case.
Schoofs2016
(immunotherapy)
-
3BNC117: Donor EB179 was a long-term non-progressor with high serum neutralization breadth and potency. 8 B-cell clones produced Abs, including 179NC75, which had the highest neutralization, especially to Clade B viruses, neutralizing 70% of a clade-B pseudovirus panel and 6 out of 9 cross-clade Env pseudoviruses as opposed to bNAb 3BNC117's neutralizing 7/9 of the same psuedoviral panel.
Freund2015
(neutralization, broad neutralizer)
-
3BNC117: A panel of antibodies was tested for binding, stability, and ADCC activity on HIV-infected cells. The differences in killing efficiency were linked to changes in binding of the antibody and the accessibility of the Fc region when bound to infected cells. Ab 3BNC117 had strong ADCC.
Bruel2016
(effector function, binding affinity)
-
3BNC117: This review summarized bNAb immunotherapy studies. Several bnAbs have been shown to decrease viremia in vivo, and are a prospect for preventative vaccinations. bNAbs have 3 possible immune effector functions: (1) directly neutralizing virions, (2) mediating anti-viral activity through Fc-FcR interactions, and (3) binding to viral antigen to be taken up by dendritic cells. In contrast to anti-HIV mAbs, antibodies against host cell CD4 and CCR5 receptors (iMab and PRO 140) are hindered by their short half-life in vivo. MAb 3BNC117 was the first to be tested in a human trial and has also shown promising results in studies in humanized mice and macaques.
Halper-Stromberg2016
(immunotherapy, review)
-
3BNC117: The rate of maturation and extent of diversity for the VRC01 lineage were characterized through longitudinal sampling of peripheral B cell transcripts from donor 45 over 15 years and co-crystal structures. VRC01-lineage clades underwent continuous evolution, with rates of ˜2 substitutions per 100 nucleotides per year, comparable with HIV-1 evolution. 39 VRC01-lineage Abs segregated into three major clades, and all Abs from donor 45 contained a cysteine at position 98 (99 in some sequences due to a 1-aa insertion) which was used as a signature to assess membership in the VRC01 lineage. Of 1,041 curated NGS sequences assigned to the VRC01 lineage, six did not contain the cysteine while 1,035 did (99.4%). Structural comparison of 3BNC117 heavy and light chains and binding surfaces were reported (Table-S5).
Wu2015
(structure, antibody lineage)
-
3BNC117: Four bNAbs (VRC01, VRC01-LS, 3BNC117, and 10-1074) were administered, singly or in combination, to macaques, followed by weekly challenges with clade B SHIVAD8. In all cases, the administration of MAbs delayed virus acquisition. Control animals required 2 to 6 challenges before becoming infected, while animals receiving VRC01 required 4–12 challenges; 3BNC117 required 7–20 challenges; 10-1074 required 6–23 challenges; and VRC01-LS required 9–18 challenges. Animals that received a single antibody infusion resisted infection for up to 23 weekly challenges.
Gautam2016
(immunotherapy)
-
3BNC117: This study isolated 4 novel antibodies that bind the CD4 binding site of Env. Population-level analysis classified a diverse group of CD4bs antibodies into two types: CDR H3-dominated or VH-gene-restricted, each with distinct ontogenies. Structural data revealed that neutralization breadth was correlated with angle of approach of the antibodies to the CD4 binding region. 3BNC117 was one of the antibodies in the VH gene restricted, 8ANC131-like class.
Zhou2015
(neutralization, structure, antibody lineage, broad neutralizer)
-
3BNC117: Double, triple or quadruple combinations of fifteen bNAbs that target 4 distinct epitope regions: the CD4 binding site (3BNC117, VRC01, VRC07, VRC07-523, VRC13), the V3-glycan supersite (10–1074, 10-1074V, PGT121, PGT128), the V1/V2-glycan site (PG9, PGT145, PGDM1400, CAP256-VRC26.08, CAP256-VRC26.25), and the gp41 MPER epitope (10E8) were studied. Their neutralization potency and breadth were assayed against a panel of 200 acute/early subtype C strains, and compared to a novel, highly accurate predictive mathematical model (no-overlap Bliss Hill model, CombiNaber tool, LANL HIV Immunology database). These data were used to predict the best combinations of bNAbs for immunotherapy.
Wagh2016
(neutralization, immunotherapy)
-
3BNC117: 3BNC117 infusion in humans was well tolerated, demonstrated favorable pharmacokinetics, and reduced the viral load in HIV-1-infected individuals. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days, with significantly reduced viremia. Contact residues and several mutations in gp120 after immunotherapy are mentioned for different subjects, including G459D, Q363H, S461D and S274Y.
Caskey2015
(immunotherapy)
-
3BNC117: This study reports the generation of a human CD4- and human CCR5-expressing transgenic luciferase reporter mouse that facilitates measurement of peritoneal and genitomucosal HIV-1 pseudovirus entry in vivo for the preclinical evaluation of prophylactic or vaccine candidates. The results showed that passive transfer of neutralizing Abs can protect HIV-LucTG mice from cervicovaginal infection with HIV-1 pseudoviruses.
Gruell2013
(genital and mucosal immunity, immunotherapy)
-
3BNC117: A gp140 trimer mosaic construct (MosM) was produced based on M group sequences. MosM bound to CD4 as well as multiple bNAbs, including VRC01, 3BNC117, PGT121, PGT126, PGT145, PG9 and PG16. The immunogenicity of this construct, both alone and mixed together with a clade C Env protein vaccine, suggest a promising approach for improving NAb responses.
Nkolola2014
(vaccine antigen design)
-
3BNC117dRU3: The ontogeny of VRC01 class Abs was determined by enumerating VRC01-class characteristics in many donors by next-gen sequencing and X-ray crystallography. Analysis included VRC01 (donor NIH 45), VRC-PG04 (donor IAVI 74), VRC-CH31 (donor 0219), 3BNC117 (donor RU3), 12A21 (donor IAVI 57), and somatically related VRC-PG19,19b, 20, 20b MAbs from donor IAVI 23. Despite the sequence differences of VRC01-class Abs, exceeding 50%, Ab-gp120 cocrystal structures showed VRC01-class recognition to be remarkably similar. It is reported that glutamic acid to glutamine mutation at residue 96 decreased the binding affinity to 10 fold in this Ab.
Zhou2013a
(antibody sequence, structure, antibody lineage)
-
3BNC117: Next generation sequencing was applied to a new donor C38 (different from donor NIH45) to identify VRC01 class bNAbs. VRC01 class heavy chains were selected through a cross-donor phylogenetic analysis. VRC01 class light chains were identified through a five-amino-acid sequence motif. (CDR L3 length of 5 amino acids and Q or E at position 96 (Kabat numbering) or position 4 within the CDR L3 sequence.) 3BNC117 was used to compare the heavy & light chain sequences as a template of VRC01 class Ab. Its crystal structure was studied.
Zhu2013a
(antibody sequence, structure)
-
3BNC117: Profound therapeutic efficacy of PGT121 and PGT121-containing monoclonal antibody cocktails was demonstrated in chronically SHIV-SF162P3 infected rhesus monkeys. Cocktails included 1, 2, and 3 mAb combinations of PGT121, 3BNC117 and b12. Cocktails including PGT121 were efficient, 3BNC117 alone resulted in only a transient small reduction of plasma viral loads.
Barouch2013a
(immunotherapy)
-
3BNC117: A computational method to predict Ab epitopes at the residue level, based on structure and neutralization panels of diverse viral strains has been described. This method was evaluated using 19 Env-Abs, including 3BNC117, against 181 diverse HIV-1 strains with available Ab-Ag complex structures.
Chuang2013
(computational prediction)
-
3BNC117: "Neutralization fingerprints" for 30 neutralizing antibodies were determined using a panel of 34 diverse HIV-1 strains. 10 antibody clusters were defined: VRC01-like, PG9-like, PGT128-like, 2F5-like, 10E8-like and separate clusters for b12, CD4, 2G12, HJ16, 8ANC195. This mAb belongs to 10E8-like cluster.
Georgiev2013
(neutralization)
-
3BNC117: Neutralizing antibody response was studied in elite controller. Subject VC10042 is an African American male, infected with clade B for 2 decades (since 1984) without any signs of disease and no antiretroviral treatment. The neutralizing activity of autologous CD4bs NAbs was very similar to that of NIH45-46W, but very different from other anti-CD4bs MAbs tested. The viral autologous variants that were resistant to neutralization by autologous and most bnMAbs tested had an extremely rare R272/N368 combination. This mutation was shown in the study to impart a fitness cost to the virus.
Sather2012
(autologous responses, elite controllers and/or long-term non-progressors, neutralization, escape, polyclonal antibodies)
-
3BNC117: A computational tool (Antibody Database) identifying Env residues affecting antibody activity was developed. As input, the tool incorporates antibody neutralization data from large published pseudovirus panels, corresponding viral sequence data and available structural information. The model consists of a set of rules that provide an estimated IC50 based on Env sequence data, and important residues are found by minimizing the difference between logarithms of actual and estimated IC50. The program was validated by analysis of MAb 8ANC195, which had unknown specificity. Predicted critical N-glycosylation for 8ANC195 were confirmed in vitro and in humanized mice. The key associated residues for each MAb are summarized in the Table 1 of the paper and also in the Neutralizing Antibody Contexts & Features tool at Los Alamos Immunology Database.
West2013
(glycosylation, computational prediction)
-
3BNC117: Identification of broadly neutralizing antibodies, their epitopes on the HIV-1 spike, the molecular basis for their remarkable breadth, and the B cell ontogenies of their generation and maturation are reviewed. Ontogeny and structure-based classification is presented, based on MAb binding site, type (structural mode of recognition), class (related ontogenies in separate donors) and family (clonal lineage). This MAb's classification: gp120 CD4-binding site, CD4-mimicry by heavy chain, VRC01 class, 3BNC117 family.
Kwong2012
(review, structure, broad neutralizer)
-
3BNC117: This review discusses how analysis of infection and vaccine candidate-induced antibodies and their genes may guide vaccine design. This MAb is listed as CD4 binding site bnAb, isolated after 2009 by fluorescence-activated cell sorting (FACS) and 454 deep sequencing.
Bonsignori2012b
(vaccine antigen design, vaccine-induced immune responses, review)
-
3BNC117: Somatic hypermutations are preferably found in CDR loops, which alter the Ab combining sites, but not the overall structure of the variable domain. FWR of CDR are usually resistant to and less tolerant of mutations. This study reports that most bnAbs require somatic mutations in the FWRs which provide flexibility, increasing Ab breadth and potency. To determine the consequence of FWR mutations the framework residues were reverted to the Ab's germline counterpart (FWR-GL) and binding and neutralizing properties were then evaluated. 3BNC117, a CD4Bs Ab, was among the 17 bnAbs which were used in studying the mutations in FWR. Crystal structure of 3BNC117/gp120 was compared with 3BNC60 in the context of insertion mutations in FWR and its role in increasing neutralizing activities.
Klein2013
(neutralization, structure, antibody lineage)
-
3BNC117: This study shows that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target CD4BS. However, the elimination of a conserved NLGS at Asn276 in Loop D and the NLGS at positions 460 and 463, located in variable region 5 of Env increased the binding and activation of VRC01 and NIH45-46. 3BNC117 was studied as anti-CD4BS bnAbs belongs to VRC01 class.
McGuire2013
(neutralization, antibody lineage)
-
3BNC117: Existing structural and sequence data was analyzed. A set of signature features for potent VRC01-like (PVL) and almost PVL abs was proposed and verified by mutagenesis. 3BNC117 has been referred as a PVL in discussing the breadth and potency of antiCD4 abs.
West2012a
(antibody lineage)
-
3BNC117: A single-cell Ab cloning method is described to isolate neutralizing Abs using truncated gp160 transfected cells as bait. Among the 15 Abs reported, only two are found to be broadly neutralizing and bind to a novel conformational HIV-1 spike epitope.
Klein2012
(neutralization)
-
3BNC117: Several antibodies including 10-1074 were isolated from B-cell clone encoding PGT121, from a clade A-infected African donor using YU-2 gp140 trimers as bait. These antibodies were segregated into PGT121-like (PGT121-123 and 9 members) and 10-1074-like (20 members) groups distinguished by sequence, binding affinity, carbohydrate recognition, neutralizing activity, the V3 loop binding and the role of glycans in epitope formation. The epitopes for both groups contain a potential N-linked glycosylation site (PNGS) at Asn332gp120 and the base of the V3 loop of the gp120 subunit of the HIV spike. However, the 10-1074–like Abs required an intact PNGS at Asn332gp120 for their neutralizing activity, whereas PGT121-like antibodies were able to neutralize some viral strains lacking the Asn332gp120 PNGS. 3BNC117 was used as a control in virus neutralization assay. Detail information on the binding and neutralization assays are described in the figures S2-S11.
Mouquet2012a
(glycosylation, neutralization, binding affinity)
-
3BNC117: Neutralization activity was compared against MAb 10E8 and other broad and potent neutralizers in a 181-isolate Env-pseudovirus panel. 2F5 neutralized 84% of viruses at IC50 <50 μg/ml and 77% of viruses at IC50 <1 μg/ml, compared with 98% and 72% of MAb 10E8, respectively.
Huang2012a
(neutralization)
-
3BNC117: The sera of 113 HIV-1 seroconverters from three cohorts were analyzed for binding to a set of well-characterized gp120 core and resurfaced stabilized core (RSC3) protein probes, and their cognate CD4bs knockout mutants. 3BNC117 bound very strongly to the gp120 core and RSC3, strongly bound to gp120 core D368R, weakly bound to RSC3/G367R but did not bind to RSC3 Δ3711, and RSC3 Δ3711/P363N.
Lynch2012
(binding affinity)
-
3BNC117: 576 new HIV antibodies were cloned from 4 unrelated individuals producing expanded clones of potent broadly neutralizing CD4bs antibodies that bind to 2CC core. In order to amplify highly somatically mutated immunoglobulin genes, new primer set with 5' primer set further upstream from the potentially mutated region was used. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 IgH chain amino acids and arose independently from two related IgH genes. 3BNC117 arises from IgVH1-2 and IgVK1D-33 germline genes and neutralized 100% of 118 isolates representing major HIV-1 clades, and 1/5 VRC01-resistant isolates, with IC50 <50μg/ml. Only 17 of the viruses tested were more sensitive to VRC01 than to 3BNC117. NIH45-46, a new variant of VRC01, was more potent than VRC01 on 62 of the viruses tested but still less potent than 3BNC117. 3BNC117 was polyreactive - reacted with dsDNA and LPS, but not with ssDNA or insulin.
Scheid2011
(antibody generation, neutralization, antibody sequence, broad neutralizer)
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Peter D. Kwong and John R. Mascola. Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies. Immunity, 37(3):412-425, 21 Sep 2012. PubMed ID: 22999947.
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Peter D. Kwong and John R. Mascola. HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure. Immunity, 48(5):855-871, 15 May 2018. PubMed ID: 29768174.
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LaBranche2018
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Valérie Lorin, Ignacio Fernández, Guillemette Masse-Ranson, Mélanie Bouvin-Pley, Luis M. Molinos-Albert, Cyril Planchais, Thierry Hieu, Gérard Péhau-Arnaudet, Dominik Hrebik, Giulia Girelli-Zubani, Oriane Fiquet, Florence Guivel-Benhassine, Rogier W. Sanders, Bruce D. Walker, Olivier Schwartz, Johannes F. Scheid, Jordan D. Dimitrov, Pavel Plevka, Martine Braibant, Michael S. Seaman, François Bontems, James P. Di Santo, Félix A. Rey, and Hugo Mouquet. Epitope Convergence of Broadly HIV-1 Neutralizing IgA and IgG Antibody Lineages in a Viremic Controller. J. Exp. Med., 219(3), 7 Mar 2022. PubMed ID: 35230385.
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Mandizvo2022
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Mishra2020a
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Sliepen2019
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Spencer2021
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Wang2019
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Wang2020
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Ward2019
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Webb2015
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Wiehe2018
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Wu2015
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Wu2016
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Yang2022
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Zhang2022
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Zhou2013a
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Zhou2015
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Richard2018
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Displaying record number 2777
Download this epitope
record as JSON.
MAb ID |
10-1074 (10.1074) |
HXB2 Location |
Env |
Env Epitope Map
|
Author Location |
Env |
Epitope |
|
Subtype |
A |
Ab Type |
gp120 V3 // V3 glycan (V3g) |
Neutralizing |
P (tier 2) View neutralization details |
Contacts and Features |
View contacts and features |
Species
(Isotype)
|
human(IgG) |
Patient |
Donor 17 |
Immunogen |
HIV-1 infection |
Keywords |
acute/early infection, anti-idiotype, antibody binding site, antibody generation, antibody interactions, antibody lineage, antibody polyreactivity, antibody sequence, assay or method development, autologous responses, binding affinity, broad neutralizer, chronic infection, co-receptor, complement, computational prediction, contact residues, early treatment, effector function, elite controllers and/or long-term non-progressors, enhancing activity, escape, glycosylation, HAART, ART, HIV reservoir/latency/provirus, immunoprophylaxis, immunotherapy, mutation acquisition, neutralization, polyclonal antibodies, review, SIV, structure, subtype comparisons, supervised treatment interruptions (STI), therapeutic vaccine, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity, viral fitness and/or reversion |
Notes
Showing 82 of
82 notes.
-
10-1074: Eighty clusters of overlapping epitopes that could bind to MHC Class II HLA-DR1*01:01 (DR1) allele were identified by LC-MS/MS using a cell-free processing system that incorporated soluble DR1, HLA-DM (DM), cathepsins, and full-length protein antigens (Gag, Pol, Env, Vif, Tat, Rev, and Nef). Sixteen of Env CD4+ T cell epitopes identified in this study, which were primarily located in the vicinity of the gp120/gp41 interface or the CD4bs, were assessed for overlap with bnAb binding footprints. Only unglycosylated TGE320-328 (TGEIIGDIR) overlapped with the binding footprint of Apex-targeting bnAb 10-1074.
Sengupta2023
(antibody binding site)
-
10-1074: This preview summarizes the findings of Doud2017, Dingens2017, and Dingens2019 where all possible point mutation escapes from binding nAbs were mapped using a screen of single amino acid changes of soluble Env ectodomain that were then grown and exposed to bnAbs. A loss of interaction/binding to the bnAb suggested neutralization resistant Env and these were deep sequenced, giving an atlas of escape pathways the virus might take. Escape mutants were found to mostly overlap with the 5 structural epitopes (antigen binding regions) of Env even though many of them are not reported in nature. Two additional sets of mutations were found in (1) contact residues that do not affect neutralization and (2) residues outside the 5 structural epitopes. These studies will provide a third characteristic to add to successful bnAb generation besides breadth and potency - "non-susceptibility to escape". Combination therapy trials like those of PGT121 and 10-1074, both of which target the glycosylation supersite N332, would also benefit from an understanding of their antigenic escape profile.
Ward2019
(review)
-
10-1074: The study describes the generation, crystal structure, and immunogenic properties of a native-like Env SOSIP trimer based on a group M consensus (ConM) sequence. A crystal structure of ConM SOSIP.v7 trimer together with nAbs PGT124 and 35O22 revealed that ConM SOSIP.v7 is structurally similar to other Env trimers. In rabbits, the ConM SOSIP trimer induced serum nAbs that neutralized the autologous Tier 1A virus (ConM from 2004) and a related Tier 1B ConS virus (ConM from 2001). These responses target the trimer apex and were enhanced when the trimers were presented on ferritin nanoparticles. The neutralization of ConM and ConS pseudoviruses was tested against a large panel of nAbs and non-nAbs (2219, 2557, 3074, 3869, 447-52D, 830A, 654-30D, 1008-30D, 1570D, 729-30D, F105, 181D, 246D, 50-69D, sCD4, VRC01, 3BNC117, CH31, PG9, PG16, CH01, PGDM1400, PGT128, PGT121, 10-1074, PGT151, VRC43.01, 2G12, DH511.2_K3, 10E8, 2F5, 4E10); most nAbs were able to neutralize these pseudoviruses. Soluble ConM trimers were able to weakly activate B cells expressing PGT121 and PG16 BCRs but were inactive against those expressing VRC01 and PGT145. In contrast, at the same molar amount of trimers, the ConM SOSIP.v7-ferritin nanoparticles activated all 4 B cells efficiently. Binding of bnAbs 2G12 and PGT145 and non-nAbs F105 and 19b to ConM SOSIP.v7 trimer and SOSIP showed that the ferritin-bound trimer bound more avidly than the soluble trimer. This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences, and such immunogens might be suitable vaccine components to prime and/or boost desirable nAb responses.
Sliepen2019
(neutralization, vaccine antigen design)
-
10-1074: A SHIV carrying a highly neutralization-sensitive Env (SHIVCNE40) was passaged in macaques. SHIVCNE40 developed enhanced replication kinetics associated with neutralization resistance against autologous serum, CD4-Ig, and several nAbs (17b, 3BNC117, N6, PGT145, PGT121, PGT128, 35O22, 2F5, 10E8). A gp41 substitution, E658K, was the major determinant for this resistance. However, this mutation didn’t disrupt the binding of SHIVCNE40 with assayed nAbs (17b, N6, VRC01, b12, PGT145, 10-1074, 35O22). Structural modeling and functional verification indicate that the substitution disrupts an intermolecular salt bridge with the neighboring protomer, particularly K601, thereby promoting fusion and facilitating immune evasion. This effect is applicable across many HIV-1 viruses of diverse subtypes. These results highlight the critical role of gp41 in shaping the neutralization profile and conformation of Env during viral adaptation. The unique intermolecular salt bridge could potentially be utilized for rational vaccine design involving more stable HIV-1 Env trimers.
Wang2019
(mutation acquisition, neutralization, structure)
-
10-1074: A panel of 30 contemporary subtype B pseudoviruses (PSVs) was generated. Neutralization sensitivities of these PSVs were compared with subtype B strains from earlier in the pandemic using 31 nAbs (PG9, PG16, PGT145, PGDM1400, CH02, CH03, CH04, 830A, PGT121, PGT126, PGT128, PGT130, 10-1074, 2192, 2219, 3074, 3869, 447-52D, b12, NIH45-46, VRC01, VRC03, 3BNC117, HJ16, sCD4, 10E8, 4E10, 2F5, 7H6, 2G12, 35O22). A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 nAbs for the contemporary, as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the nAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A metaanalysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.
Wieczorek2023
(neutralization, viral fitness and/or reversion)
-
10-1074:This study identified a B cell lineage of bNAbs in an HIV-1 elite post-treatment controller (ePTC; donor: PTC-005002). Circulating viruses in PTC escaped bNAb pressure but remained sensitive to autologous neutralization by other Ab populations. 10-1074 was used as a reference control IgG. Inhibition of EPTC112 binding to SOSIP was mainly evidenced with anti-V3-glycan bNAb 10-1074 (55%–77% blocking range).
Molinos-Albert2023
(binding affinity)
-
10-1074: A panel of 58 mAbs was cloned from a rhesus macaque immunized with envelope glycoprotein immunogens developed from HIV-1 clade B-infected human donor VC10014. Neutralizing mAbs predominantly targeted linear epitopes in the V3 region in the cradle orientation (V3C), with others targeting the V3 ladle orientation (V3L), the CD4 binding site, C1, C4, or gp41. Nonneutralizing mAbs bound C1, C5, or undetermined gp120 conformational epitopes. Neutralization potency strongly correlated with the magnitude of binding to infected primary macaque splenocytes and to the level of ADCC, but did not correlate with ADCP. MAbs were traced to 23 of 72 functional IgHV germline alleles. Neutralizing V3C mAbs displayed minimal nucleotide SHM in the H chain V region (3.77%), indicating that relatively little affinity maturation was needed to achieve in-clade neutralization breadth. This study underscores the polyfunctional nature of vaccine-elicited tier 2-neutralizing V3 Abs and demonstrates partial reproduction of a human donor’s Ab response through nonhuman primate vaccination. MAb 10-1074 was used in binding assays, and as a positive control for ADCC activity.
Spencer2021
(effector function, vaccine antigen design, binding affinity)
-
10-1074: The study isolated 3 new V3-glycan antibody lineages (DH270, DH272, DH475) from donor CH848, who was followed for 5 years starting from the time of transmission. The DH272 and DH475 lineages had neutralization patterns that likely selected for observed viral escape variants, which, in turn, stimulated the DH270 lineage to potent neutralization breadth. DH270 antibodies were recovered from memory B cells at all three sampling times (weeks 205, 232, and 234 post-infection). Like some previously-characterized Abs (PGT121, PGT128, 10-1074), the DH270 lineage mAbs bound to Env N332, and their neutralization was reduced or abrogated by mutation of this residue. 10-1074 neutralized 136/207 heterologous pseudoviruses with IC50 value of <50 μ/ml and demonstrated an inverse correlation between potency and V1 length.
Bonsignori2017
(neutralization, broad neutralizer)
-
10-1074: This study explored the basis of the neutralization resistance of tier 3 virus 253-11 (subtype CRF02_AG). Virus 253-11 was resistant to neutralization by 17b, b12, VRC03, F105, SCD4, CH12, Z13e1, PG16, PGT145, 2G12, PGT121, PGT126, PGT128, PGT130, 39F, F240, and 35O22; the virus was sensitive to 3BNC117, NIH45-46G54W, VRC01, 10E8, 2F5, 4E10, PG9, VRC26.26, 10-1074, and PGT151. Virus 253-11 was strikingly resistant to most tested antibodies that target V3/glycans, despite possessing key potential N-linked glycosylation sites, especially N301 and N332, needed for the recognition of this class of antibodies. The resistance of 253-11 was not associated with an unusually long V1/V2 loop, nor with polymorphisms in the V3 loop and N-linked glycosylation sites. The 253-11 MPER was rarely recognized by sera, but was more often recognized in a chimera consisting of a HIV-2 backbone with the 253-11 MPER, suggesting steric or kinetic hindrance of the MPER. Mutations in the 253-11 MPER previously reported to increase the lifetime of the prefusion Env conformation (Y681H, L669S), decreased the resistance of 253-11 to several mAbs, presumably destabilizing its otherwise stable, closed trimer structure. A crystal structure of a recombinant 253-11 SOSIP trimer revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact form around the trimer axis.
Moyo2018
(neutralization, structure)
-
10-1074: This study assessed the ability of single bNAbs and triple bNAb combinations to mediate polyfunctional antiviral activity against a panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies in nonhuman primate models. Most bnAbs assayed were capable of mediating both neutralizing and nonneutralizing effector functions (ADCC and ADCP) against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs was highly strain dependent. Several triple bNAb combinations were identified comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. In assays using the transmitted/founder SHIV.C.CH505, there was a correlation between the neutralization potencies and nonneutralizing effector functions of bnAbs: 10-1074 was negative for neutralization, ADCC, and binding to infected cells.
Berendam2021
(effector function, neutralization, binding affinity, broad neutralizer)
-
10-1074: The VRC01 Antibody Mediated Prevention (AMP) vaccine trials (2016-2020) showed that passively administered bnAbs could prevent HIV-1 acquisition of bnAb-sensitive viruses. Viruses isolated from AMP participants who acquired infection during the study were used to make a panel of 218 HIV-1 pseudoviruses. The majority of viruses identified were clade B and C, with clades A, D, F, G and recombinants present at lower frequencies. BnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10–1074 and 10E8v4) were tested for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998–2010), the AMP clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best antibody mixture against clade C viruses, and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. The AMP placebo virus panel represents a resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs.
Mkhize2023
(assay or method development, neutralization, immunotherapy)
-
10-1074: To characterize the persistence and phenotypic properties of HIV Env over time, blood and lymphoid samples were obtained at 2 timepoints from 8 people with HIV on suppressive ART. Single genome amplification and sequencing was performed on env to understand genetic diversity clonal expansion. A subset of envs were used to generate pseudovirus particles to assess sensitivity to autologous plasma IgG and bnAbs, and neutralization was assayed against a panel of 5 bnAbs (VRC01, 10E8, PGT121, 10-1074, 3BNC117) and the trispecific N6/PGDM1400x10E8. Identical env sequences indicating clonal expansion persisted between timepoints and within multiple T-cell subsets. At both timepoints, CXCR4-tropic (X4) Envs were more prevalent in naive and central memory cells; the proportion of X4 Envs did not significantly change in each subset between timepoints. Autologous purified plasma IgG showed variable neutralization of Envs, with no significant difference in neutralization between R5 and X4 Envs. X4 Envs were more sensitive to neutralization with clinical bnAbs, with CD4-binding site bnAbs demonstrating high breadth and potency against Envs. These data suggest the viral reservoir was predominantly maintained over time through proliferation of infected cells. The humoral immune response to Envs within the latent reservoir was variable between persons. The study also found that coreceptor usage can influence bNAb sensitivity and may need to be considered for future bNAb immunotherapy approaches.
Gartner2023
(co-receptor, neutralization, HAART, ART, HIV reservoir/latency/provirus, polyclonal antibodies)
-
10-1074: This paper comprehensively defined the effect of every viable single aa mutation in the ectodomain and transmembrane domain of BG505.T332N Env on binding by 9 individual bnAbs targeting 5 epitope classes (VRC01, 3BNC117, PGT121, 10-1074, PG9, PGT145, PGT151, VRC34.01, and 10E8), as well as by a mixture of 3BNC117 and 10-1074. Escape mutations mostly occurred in a small subset of structurally-defined contacts within <4 Å and at sites within 5-10 Å of the Ab. Escape from both V3-targeting bnAbs, PGT121 and 10-1074, occurred at similar sites, especially in and near the GDIR and N332 glycosylation motifs. There were also Ab-specific differences in escape sites as well as a larger effect magnitude for 10-1074. Env sites with the largest cumulative mutational impact on 10-1074 binding, either individually or in combination with 3BNC117, were D325, N332, and S334. Of 16 point mutations assessed, H330R and D325E mutations had the greatest effect on neutralization by 10-1074 with respective IC50 value fold-increases of 35.1 and 27.2, relative to wildtype. See LANL Features and Contacts database for more details.
Dingens2019
(antibody binding site, neutralization, escape, contact residues)
-
10-1074: This study reports on bispecific antibodies in which one arm is a single-chain (scFv) form of a V2-glycan antibody (VRC26.25 or PGT145), and the other arm is a V3-glycan Fab (10-1074, PGT121, or PGT128). A linker was used consisting of 10 repeats of tetraglycine-serine (10GS); additionally, KIH (knob in hole) mutations were introduced for stabilization. Some of these bispecific antibodies are markedly more potent than their parental bNAbs, likely because they simultaneously engage both the V2-apex and V3-glycan epitopes of Env.
Davis-Gardner2020
(neutralization, broad neutralizer)
-
10-1074: This study aimed to define properties shared by transmitted viruses by comparing antigenic and functional properties of envelope glycoproteins of viral variants isolated during primary infection in 27 patients belonging to 8 transmission clusters. The neutralization of the 27 pseudotyped viruses was assayed with 8 human bnAbs targeting various regions of the virus. The infectious properties of the viruses was assessed by measuring their infectivity and sensitivity to entry inhibitors. Transmitted viruses from the same transmission chain shared many properties, including similar neutralization profiles, sensitivity to inhibitors, and infectivity. All transmitted viruses were CCR5-tropic, sensitive to maraviroc, and resistant to soluble forms of CD4, irrespective of cluster. They were also generally sensitive to bnAbs that target V3 (10-1074, PGT121), CD4bs (3BNC117, NIH45-46G54W), and MPER region (10E8), suggesting that the loss of these epitopes may affect a virus’s capacity to be transmitted. The viruses were somewhat less sensitive to bnAbs targeting the V1V2 region (PG9, PGT145) and gp120/gp41 interface (8ANC195). These data suggest that the transmission bottleneck is governed by selective forces.
Beretta2018
(neutralization, acute/early infection)
-
10-1074: This study examined whether HIV-1-specific bnAbs are capable of cross-neutralizing simian immunodeficiency viruses (SIVs) from chimpanzees (n=11) or western gorillas (n=1). BnAbs directed against the epitopes at the CD4 binding site (VRC01, VRC03, VRC-PG04, VRC-CH03, VRC-CH31, F105, b13, NIH45-46G54W, 45-46m2, 45-46m7), V3 (10-1074, PGT121, PGT128, PGT135, and 2G12), and gp41-gp120 interface (8ANC195, 35O22, PGT151, PGT152, PGT158) failed to neutralize SIVcpz and SIVgor strains. V2-directed bNabs (PG9, PG16, PGT145) as well as llama-derived heavy-chain only antibodies recognizing the CD4 binding site or gp41 epitopes (JM4, J3, 3E3, 2E7, 11F1F, Bi-2H10) were either completely inactive or neutralized only a fraction of SIVcpz strains. In contrast, neutralization of SIVcpz and SIVgor strains was achieved with low-nanomolar potency by one antibody targeting the MPER region of gp41 (10E8), as well as functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, CD4-218.3-E51-mim2), mono- and bispecific anti-human CD4 mAbs (iMab, PG9-iMab, PG16-iMab, LM52, LM52-PGT128), and CCR5 receptor mAbs (PRO140, PRO140-10E8). Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5, and neutralized SIVcpz in chimpanzee CD4+ T cells. These findings provide new insight into the protective capacity of anti-HIV-1 bnAbs and identify candidates for further development to combat SIV infection.
Barbian2015
(neutralization, SIV, binding affinity)
-
10-1074: A recombinant native-like Env SOSIP trimer, AMC009, was developed based on viral founder sequences of elite neutralizer H18877. The subtype B AMC009 Env was defined as a Tier 2 virus based on a neutralization assay against well known nAbs (VRC01, 3BNC117, CH31, CH01, PG9, PG16, PGDM1400, 10-1074, PGT128, PGT121, PGT151, VRC34.01, 2G12, 2F5, 4E10, DH511.2.K3_4, 10E8, and the mAb mixture CH01-31).The AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bnAb epitopes. Its overall structure was similar to that of BG505 SOSIP.664, and it resembled one from another elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, AMC009 trimers did not induce autologous neutralizing antibody responses efficiently, while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the nAb activity from rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers.
Schorcht2020
(neutralization, vaccine-induced immune responses, structure)
-
10-1074: The study looked at the neutralization of subtype C Env sequences from 9 South African individuals followed longitudinally. A total of 43 Env sequences were cloned and assayed for neutralization by 12 bnAbs of various binding types (VRC07-LS, N6.LS, VRC01, PGT151, 10-1074 and PGT121, 10E8, 3BNC117, CAP256.VRC26.25, 4E10, PGDM1400, and N123-VRC34.01). Features associated with resistance to bNAbs were higher potential glycosylation sites, relatively longer V1 and V4 domains, and known signature mutations. The study found significant variability in the breadth and potency of bnAbs against circulating HIV-1 subtype C envelopes. In particular, VRC07-LS, N6.LS, VRC01, PGT151, 10-1074, and PGT121 display broad activity against subtype C variants. The results suggest that these 6 bnAbs are potent antibodies that should be considered for future antibody therapy and treatment studies targeting HIV-1 subtype C.
Mandizvo2022
(glycosylation, mutation acquisition, neutralization, immunotherapy)
-
10-1074: Structural characterization of macaque vaccine-induced mAbs Ab1303 and Ab1573 revealed a CD4bs binding mechanism that requires an occluded-open Env trimer conformation, similar to what has been observed for mAb b12. In a BG505 Env trimer binding competition assay, V3 loop-targeting 10-1074 Fab enhanced Ab1573 binding but had no effect on Ab1303 binding.
Yang2022
(antibody interactions)
-
10-1074: A macaque sequential immunization protocol with increasingly native-like V3-glycan-targeting Env trimers multimerized onto virus-like particles elicited multiple on-target mAbs with heterologous, yet generally weak, neutralization activity and minimal protection in a subsequent intrarectal heterologous challenge with SHIVDH12-V3AD8. The priming immunogen was RC1-4fill (clade A/E, RC1 with 4 additional glycans), a low affinity Env trimer with additional glycans to facilitate V3-glycan targeting and mask BG505 glycan hole, while the boosting immunogens were 11MUTB-4fill (clade A/E), B41-5MUT or B41 wildtype (clade B), AMC011/Du422 (clade B/C), and consensus group M/consensus clade C Env trimers. Rabbits were also immunized once with RC1-4 fill-VLP and produced V3-targeting mAbs with binding poses distinct from the known V3-targeting bnAbs (10-1074, PGT135, PGT128 and BG18). In a RC1 binding assay, 10-1074 Fab competed substantially with isolated macaque mAbs (Ab1271, Ab1289, Ab1368, Ab1415, Ab1456, Ab1457, and Ab1461), bnAb PGT128, itself, and a shared PGT121/10-1074 inferred germline precursor. Modest to moderate competition was also observed between 10-1074 Fab and isolated macaque mAb Ab1573 and bnAbs IOMA and PGT145. After priming, serum from the 8 immunized macaques also displayed strong competition with V3-glycan-targeting 10-1074 but this effect diminished after each boost, despite increasing serum responses to RC1. This suggests increasing off-target responses as the immunization protocol progressed, consistent with nsEMPEM observations.
Escolano2021
(antibody interactions, vaccine antigen design, vaccine-induced immune responses)
-
10-1074: The study assessed the breadths and potencies of 14 bnAbs against 36 viruses reactivated from peripheral blood CD4+ T cells from ARV-treated HIV-infected individuals by using paired neutralization and infected cell binding assays. Infected cell binding correlated with virus neutralization for 10 of 14 antibodies (VRC01, VRC07-523, 3BNC117, N6, PGT121, 10-1074, PGDM1400, PG9, 10E8, and 10E8v4-V5R-100cF). For example, the correlation for 3BNC117 had r=0.82 and P<0.0001. Heterogeneity was observed, however, with a lack of significant correlation for 2G12, CAP256.VRC26.25, 2F5, and 4E10. The study also performed paired infected cell binding and ADCC assays by using two reservoir virus isolates in combination with 9 bNAbs, and the results were consistent with previous studies indicating that infected cell binding is moderately predictive of ADCC activity for bNAbs with matched Fc domains. These data provide guidance on the selection of antibodies for clinical trials.
Ren2018
(effector function, neutralization, binding affinity, HIV reservoir/latency/provirus)
-
10-1074: A panel of 33 CRF02_AG pseudoviruses was generated from HIV-1-infected individuals during early stages of infection. Samples represented a 15-year period 1997-2012. These viruses were best neutralized by the CD4bs-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the MPER-directed bnAb 10E8 in terms of both potency and breadth. There was a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Neutralization by 8ANC195 was also assayed. Combinations of antibodies were predicted by the CombiNaber tool to achieve full coverage across this subtype. There was increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the timespan sampled.
Stefic2019
(neutralization, acute/early infection, subtype comparisons)
-
10-1074: 14/17 cloned mAbs from mice, immunized with either modified native-like soluble Env trimer immunogen RC1 or RC1-4fill, and 32/38 cloned mAbs from macaques, immunized once with RC1-4fill multimerized on virus-like particles bound to the desired V3-glycan patch with diverse binding mechanisms. Germline usage and CDR sequence and length were identified for all 55 mAbs but only those with published functional characterization were included in this database. In macaques, these non-neutralizing mAbs had sequence and structural similarities to inferred germline precursors of bnAbs that target V3-glycan patch like 10-1074 including longer light chain CDRs, CDRL3 QXXDSS & SYAG motifs, and CDRL1 NIG-like motifs. Compared to parental immunogen 11MUTB, both RC1 and RC1-4fill have N156 glycan deletion to facilitate V3-glycan patch binding while RC1-4fill also has glycans added at N230, N241, N289 and N344 to mask BG505-specific glycan hole. Bioinformatic analysis demonstrated that the absence of the N156 potential N-linked glyscolation site (PNGS) enhances neutralization, while the absence of N301 or N137 PNGS reduces neutralization, by bnAb 10-1074. 10-1074 efficiently bound RC1, RC1-4fill, 11MUTB, 10MUT and BG505. Compared to a known crystal structure of 10-1074 complexed with BG505, the V1 loop of RC1 was shown to have increased interactions with 10-1074 CDRH3 in a generated structure (PDB 6ORN). 10-1074 was observed to make contact with RC1 GDIR motif using its CDRH3, CDRL1, and CDRL3 and to make contact with N332 glycan using its CDRL1, FRWL3, CDRH2 and CDRH3. The shared inferred germline (iGL) of PGT121 and 10-1074 bound to RC1 and 11MUTB with similar affinities (KD values both approx. 50 μM).
Escolano2019
(antibody binding site, anti-idiotype, glycosylation, structure)
-
10-1074: The authors review Fc effector functions, which cooperatively with Fab neutralization functions, could be used passively as immunotherapeutic or immunoprophylactic agents of HIV reservoir control or even infection prevention. One effector function, antibody-dependent complement-mediated lysis (ADCML), is seen with IgG1 and IgG3 anti-V1/V2 glycan bnAbs, PG9, PG16, PGT145; but not with 2F5, 4E10, 2G12, VRC01 and 3BNC117 unless they are delivered with anti-regulators of complement activation (RCA) antibodies. Another effector function, antibody-dependent cellular cytotoxicity (ADCC) can slow disease progression by NK-mediated degranulation of infected cells that are coated by bnAbs whose Fc region is recognized by the low affinity NK receptor, FcγRIIIA (or CD16). Strong ADCC was induced by NIH45-46, 3BNC117, 10-1074, PGT121 and 10E8, with intermediate activity for PG16 and VRC01, but no ADCC activation for 12A12, 8ANC195 and 4E10. A final effector function, antibody-dependent phagocytosis (ADP) also eliminates infected cells but through phagocytosis mediated by Fc portions of coating anti-HIV antibodies interacting with other FcγR (or FcαR) on the surface of granulocytes, monocytes or macrophages. This protective mode is less well studied but bnAbs like VRC01 have been engineered to increase phagocytosis by neutrophils. Protein engineering of bispecifics against the surface of infected or reservoir virus cells has potential in the future.
Danesh2020
(antibody interactions, assay or method development, complement, effector function, immunoprophylaxis, neutralization, immunotherapy, early treatment, review, broad neutralizer, HIV reservoir/latency/provirus)
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10-1074: To understand early bnAb responses, 51 HIV-1 clade C infected infants were assayed for neutralization of a 12-virus multi-clade panel. Plasma bnAbs targeting V2-apex on Env were predominant in infant elite and broad neutralizers. In infant elite neutralizers, multi-variant infection was associated with plasma bnAbs targeting diverse autologous viruses. A panel of mAbs (PG9, PG16, PGT145, PGDM1400, VRC26.25, 10-1074, BG18, AIIMS-P01, PGT121, PGT128, PGT135, VRC01, N6, 3BNC117, PGT151, 35O22, 10E8, 4E10, F105, 17b, A32, 48d, b6, 447-52d) was assayed for their ability to neutralize Env clones from infant elite neutralizers; circulating viral variants in infant elite neutralizers were most susceptible to V2-apex bnAbs.
Mishra2020a
(neutralization, polyclonal antibodies)
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10-1074: In vertically-infected infant AIIMS731, a rare HIV-1 mutation in hypervariable loop 2 (L184F) was studied. In patient sequences, this mutation was present in the majority of clones. A panel of 6 V2 bnAbs (PG9, PG16, PGT145, PGDM1400, CAP256.25, and CH01) was assayed for neutralization of 6 patient viral clones. The AIIMS731 viral variants segregated into 4 neutralization-sensitive and 2 resistant clones; sensitive clones carried 184F, while resistant clones carried the rare 184L mutation. A large panel of bnAbs targeting non-V2 epitopes was used to assess the neutralization of the 6 patient viral variants. The bnAb panel consisted of V3/N332 glycan supersite bnAbs (10-1074, BG18, AIIMS-P01, PGT121, PGT128, and PGT135), CD4bs bnAbs (VRC01, VRC03, VRC07-523LS, N6, 3BNC117, and NIH45-46 G54W), a silent face-targeting bnAb (PG05), fusion peptide and gp120-gp41 interface bnAbs (PGT151, 35O22, and N123-VRC34.01), and MPER bnAbs (10E8, 4E10, and 2F5). All of these bnAbs had similar neutralization efficiencies for all 6 clones, suggesting that the L184F mutation was specific for viral escape from neutralization by V2 apex bnAbs. A panel of non-neutralizing mAbs (V3 loop-targeting non-nAbs 447-52D and 19b, and CD4-induced non-nAbs 17b, A32, 48d, and b6), were also assessed; 2 of the variants (the same 2 susceptible to the V2 bnAbs) showed moderate neutralization by 447-52D, 19b, 17b, and 48d. The structure of ligand-free BG505 SOSIP trimer revealed that the side chain of L184 was outward facing and did not make significant intraprotomeric interactions, but upon mutating L184 to F184, a disruption of the accessible surface between the bulky side chain of F184 on one protomer and R165 on the neighboring protomer was seen. Thus, the L184F mutation resulted in increased susceptibility to neutralization by antibodies known to target the relatively more open conformation of Env on tier 1 viruses, suggesting that the rare L184F mutation allowed Env to sample more open states resembling the CD4-bound conformation where the CCR5 binding site is exposed.
Mishra2020
(neutralization, polyclonal antibodies)
-
10-1074: This report characterizes an additional antiviral activity of some bnAbs to block HIV-1 release by tethering viral particles at the surface of infected cells in vitro in a bivalency-dependent manner. After cultivation of infected primary CD4+ T cells with individual bnAbs, supernatant p24 levels were negatively correlated with cell-associated Gag levels, Env binding and neutralization potency while cell-associated Gag levels and Env binding positively correlated with each other and individually with neutralization potency. The capacity to mediate this tethering activity varied among different classes of mAbs: 0/3 non-neutralizing mAbs, 1/5 bnAbs targeting the MPER or gp120/gp41 interface and 9/9 of the bnAbs targeting the V3 and V1/V1 loops or the CD4bs demonstrated this activity against at least 1/3 diverse viral strains (AD8, CH058 and vKB18). Five of these latter 9 bnAbs, including bnAb 10-1074 which had the most potent effect observed in study when cultivated with vKB18-infected CD4+ T cells, displayed tethering activity against all 3 strains. Surface aggregation of mature virions and 10-1074 was observed in CH058-infected primary CD4+ T cells and CHME macrophage-like cells as well as increased unspliced HIV-1 RNA in the infected CD4+ T cells.
Dufloo2022
(binding affinity)
-
10-1074: This is a report of a phase 1b therapeutic clinical trial in which humans chronically infected with HIV-1 received 7 doses of a combination of two bnAbs (3BNC117 and 10-1074), in the presence or absence of ART, which were generally safe and well-tolerated. 76% (13/17) of subjects who discontinued ART 2 days after first bnAb infusion maintained virologic suppression for at least 20 weeks. There was a moderate but significant reduction in the absolute number and relative representation of intact proviruses in the subjects treated with 3BNC117 and 10-1074 that was not seen in a parallel cohort of HIV-1-infected subjects who only received ART without bnAb therapy. The average serum half-life of 10-1074 was 20.3 days. The average serum concentration of 10-1074 at the time of rebound in individuals who remained suppressed after week 20 was 28.3 μg/ml.
Gaebler2022
(antibody interactions, immunotherapy, HAART, ART, supervised treatment interruptions (STI), broad neutralizer, chronic infection, HIV reservoir/latency/provirus)
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10-1074: This paper isolated and characterized V3-glycan bNAb Ab1485 produced by an elite neutralizing SHIVAD8-EO-infected macaque identified as CE8J. For comparison with Ab1485, the binding of V3-glycan mAb 10-1074 to BG505 was inhibited only by itself but not by mAbs 3BNC117, 8ANC117, PG9 or VRC34 which all targeted other regions of Env.
Wang2020
(antibody interactions)
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10-1074: A plant-based expression system was used to produce different glycoforms of the bnAbs PG9, PG16, 10–1074, NIH45–46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, and b12. Also produced were mutated forms (N92T) of VRC01 (mVRC01) and NIH45–46G54W (mNIH45–46G54W). The in vivo properties of these mAbs were assessed in macaques to distinguish those most likely to comprise or become a component of an affordable and efficacious immunotherapeutic cocktails. N-glycans within the VL domain impaired the plasma stability of plant-derived bnAbs. While PGT121 and b12 exhibited no immunogenicity in rhesus macaques, VRC01, 10-1074 and NIH45-46G54W elicited high titer anti-idiotypic antibodies. The results indicated that that specific mutations in certain bnAbs caused immunogenicity in macaques. Such immunogenicity in humans would potentially compromise their value for immunotherapy. CHO1-31 was used as a positive control in a neutralization assay.
Rosenberg2015
(anti-idiotype, neutralization, immunotherapy)
-
10-1074: Since cross-reactive antibodies can interfere in immunoassays, HIV-1 mAbs were tested for binding to the SARS-COV-2 spike (S) protein (SARS-COV-2 S cross-reactivity). The following 9 gp120-epitope binding HIV-1 mAbs are cross-reactive with COV-2 S: 2G12, PGT121, PGT126, PGT128, PGT145, PG9, PG16, 10-1074, and 35O22. CD4bs Abs VRC01 and VRC03 are not cross-reactive. Cross-reactivity of the 9 HIV-1 Abs was through glycoepitopes. Glycan-dependent, V3-loop-binding PGT126 and PGT128 as well as 2G12 were the strongest binders of COV-2 S and were found to be immunoreactive but incapable of neutralization or antibody-dependent enhancement (ADE).
Mannar2021
(antibody interactions, effector function, glycosylation, computational prediction, antibody polyreactivity)
-
10-1074: IgA and IgG bNAbs of 3 distinct B cell lineages were characterized in a viremic controller (pt7). Two lineages comprised only IgG+ or IgA+ blood memory B cells; the third combined both IgG and IgA clonal variants. BNAb 7-269 in the IgA-only lineage displayed the highest neutralizing capacity despite limited somatic mutation. Immunotherapy with 7-269 in humanized mice delayed viral rebound. AD8-infected cell killing by primary human natural killer (NK) cells via ADCC was observed with all pt7 bNAbs binding strongly to target cells and expressed as IgGs, except for 7-155. BNAbs in all three lineages targeted the N332 glycan supersite. Epitope mapping showed that all pt7 IgA and IgG bNAbs target the high-mannose patch centered on the N332 glycan without interacting with the V3 loop base, which contrasts with numerous bNAbs targeting the N332 supersite. The cryo-EM structure of 7-269 in complex with BG505 SOSIP revealed an epitope mainly composed of sugar residues comprising the N332 and N295 glycans; onto which 7-269 positions itself in a structurally similar way to 2G12. Binding and cryo-EM structural analyses showed that antibodies from the two other lineages interact mostly with glycans N332 and N386. Hence, multiple B cell lineages of IgG and IgA bNAbs focused on a unique HIV-1 site of vulnerability can codevelop in HIV-1 viremic controllers. Other antibodies used as controls included 10-188, 3BNC117, PGT121, PGT135, 10-1074, BG8, BG18, and SF12.
Lorin2022
(antibody binding site, binding affinity, structure)
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10-1074: Analyses of all PDB HIV1-Env trimer (prefusion, closed) structures fulfilling certain parameters of resolution were performed to classify them on the basis of (a) antibody class which was informed by parental B cells as well as structural recognition, and (b) Env residues defining recognized HIV epitopes. Structural features of the 206 HIV epitope and bNAb paratopes were correlated with functional properties of the breadth and potency of neutralization against a 208-strain panel. Broadly nAbs with >25% breadth of neutralization belonged to 20 classes of antibodies with a large number of protruding loops and high degree of somatic hypermutation (SHM). Analysis of recognized HIV epitopes placed the bNAbs into 6 categories (viz. V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide and subunit interface). The epitopes contained high numbers of independent sequence segments and glycosylated surface area. 10-1074-Env formed a distinct group within the Glycan-V3 category, Class PGT121. Data for bNAb 10-1074 complexed to fully and natively glycosylated BG505 SOSIP.664 trimer as a 3.5A crystal structure was found in PDB ID: 5T3Z.
Chuang2019
(antibody binding site, antibody interactions, neutralization, binding affinity, antibody sequence, structure, antibody lineage, broad neutralizer)
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10-1074: An elite controller patient (VA40774) was identified as having an Env V1 domain that was unusually long and contained 2 additional N-glycosylation sites and 2 additional cysteine residues, relative to HXB2. When this V1 region was put into other viral backbones, the resulting virus had lower infectivity. The long V1 domain is sufficient for partial or complete escape from neutralization by V3-glycan targeting antibodies 10-1074 and PGT121, but not by another V3-glycan bNAb (PGT128) nor by other classes of bNAbs.
Silver2019
(elite controllers and/or long-term non-progressors, neutralization)
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10-1074: This review focuses on the potential for bNAbs to induce HIV-1 remission, either alone or in combination with latency reversing agents, therapeutic vaccines, or other novel therapeutics. Ongoing human trials aimed at HIV therapy or remission are utilizing the following antibodies, alone or in combination: VRC01, VRC01-LS, VRC07-523-LS, 3BNC117, 10-1074, 10-1074-LS, PGT121, PGDM1400, 10E8.4-iMab, and SAR441236 (trispecific VRC01/PGDM1400-10E8v4). Ongoing non-human primate studies aimed to target, control, or potentially eliminate the viral reservoir are utilizing the following antibodies, alone or in combination: 3BNC117, 10-1074, N6-LS, PGT121, and the GS9721 variant of PGT121.
Hsu2021
(antibody interactions, immunotherapy, review, HIV reservoir/latency/provirus)
-
10-1074: A series of mutants was produced in the CAP256-VRC26.25 heavy chain for the purpose of avoiding the previously-identified proteolytic cleavage at position K100m. Neutralization of the mutants was tested, and the cleavage-resistant variant that showed the greatest potency was K100mA. In addition to the K100mA mutation, an LS mutation was added to the Fc portion of the heavy chain, as this change has been shown to improve the half-life of antibodies used for passive administration without affecting neutralization potency. The resulting construct was named CAP256V2LS. The pharmacokinetics of CAP256V2LS were assessed in macaques and mice, and it showed a profile similar to other antibodies used for immunotherapy. The antibody lacked autoreactivity. Structural analysis of wild-type CAP256-VRC26.25 showed that the K100m residue is not involved in interaction with the Env trimer. Previously-published neutralization data for 10-1074 were used for comparison purposes.
Zhang2022
(neutralization, immunotherapy, broad neutralizer)
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10-1074: An ART-naive HIV-controlling patient SA003 was found to have a high level of serum bNAb activity, and broadly neutralizing mAb LN01 IgG3 was isolated from patient serum. MAb 10-1074 was used as a comparison in an assay of ADCC.
Pinto2019
(effector function)
-
10-1074: In 8 ART-treated patients, latent viruses were induced by a viral outgrowth assay and assayed for their sensitivity to neutralization by 8 broadly neutralizing antibodies (VRC01, VRC07-523, 3BNC117, PGT121, 10-1074, PGDM1400, VRC26.25, 10E8v4-V5F-100cF). The patients' inducible reservoir of autologous viruses was generally refractory to neutralization, and higher Env diversity correlated with greater resistance to neutralization.
Wilson2021
(autologous responses, neutralization, HAART, ART, HIV reservoir/latency/provirus)
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10-1074: In this clinical trial, administration of PGT121 was well tolerated in both HIV-uninfected and HIV-infected individuals. PGT121 potently and transiently inhibited HIV-1 replication in viremic individuals who had PGT121-sensitive viruses at enrollment. There were several distinct viral evolutionary patterns associated with the emergence of PGT121 resistance and viral rebound. These pathways included single point mutations, multiple point mutations, and viral recombination that led to increased resistance. Loss of D325 and the glycan at N332 were specifically associated with resistance in multiple patients. In some patients, resistance to PGT121 was accompanied by resistance to other bNAbs (10-1074, PGDM1400, or 3BNC117), as measured by neutralization assays.
Stephenson2021
(glycosylation, mutation acquisition, neutralization, immunotherapy)
-
10-1074: Humanized mice were grafted with CD34+ T cells isolated from human umbilical cords, and later challenged by intra-rectal infection with HIV-1 strain NL4-3. Mice treated with a mix of 3 bNAbs (10-1074, 3BNC117, and SF12) resisted mucosal infection.
Vanshylla2021
(neutralization, immunotherapy)
-
10-1074: Novel Env pseudoviruses were derived from 22 patients in China infected with subtype CRF01_AE viruses. Neutralization IC50 was determined for 11 bNAbs: VRC01, NIH45-46G54W, 3BNC117, PG9, PG16, 2G12, PGT121, 10-1074, 2F5, 4E10, and 10E8. The CRF01_AE pseudoviruses exhibited different susceptibility to these bNAbs. Overall, 4E10, 10E8, and 3BNC117 neutralized all 22 env-pseudotyped viruses, followed by NIH45-46G54W and VRC01, which neutralized more than 90% of the viruses. 2F5, PG9, and PG16 showed only moderate breadth, while the other three bNAbs neutralized none of these pseudoviruses. Specifically, 10E8, NIH45-46G54Wand 3BNC117 showed the highest efficiency, combining neutralization potency and breadth. Mutations at position 160, 169, 171 were associated with resistance to PG9 and PG16, while loss of a potential glycan at position 332 conferred insensitivity to V3-glycan-targeting bNAbs. These results may help in choosing bNAbs that can be used preferentially for prophylactic or therapeutic approaches in China.
Wang2018a
(assay or method development, neutralization, subtype comparisons)
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10-1074: A novel CD4bs bnAb, 1-18, is identified with breadth (97% against a 119-strain multiclade panel) and potency exceeding (IC50 = 0.048 µg/mL) most VH1-46 and VH1-2 class bnAbs like 3BNC117, VRC01, N6, 8ANC131, 10-1074, PGT151, PGT121, 8ANC195, PG16 and PGDM1400. 1-18 effectively restricts viral escape better than bnAbs 3BNC117 and VRC01. As with VRC01-like Abs, 1-18 targets the CD4bs but it recognizes the epitope differently. Neutralizing activity against VRC01 Ab-class escapes is maintained by 1-18. In humanized mice infected by strain HIV-1YU2, viral suppression is also maintained by 1-18. VH1-46-derived B cell clone 4.1 from patient IDC561 produced potent, broadly active mAbs. Subclone 4.1 is characterized by a 6 aa CDRH1 insertion lengthening it from 8 to 14 aa and produces bNAbs 1-18 and 1-55. Cryo-EM at 2.5A of 1-18 in complex with BG505SOSIP.664 suggests their insertion increases inter-protomer contacts by a negatively charged DDDPYTDDD motif, resulting in an enlargement of the buried surface on HIV-1 gp120. Variations in glycosylation is thought to confer higher neutralizing activity on 1-18 over 1-55.
Schommers2020
(neutralization)
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10-1074: A dose-escalation phase 1b study in HIV-1-infected individuals to evaluate the safety, pharmacokinetics and antiretroviral activity of the combination of the Abs 3BNC117 and 10–1074 has been reported. Participants in groups 1A and 1B were virologically suppressed on ART and were randomized in a 2:1 ratio to receive one intravenous infusion of each of 3BNC117 and 10–1074 or placebo. Viremic individuals off ART were enrolled in group 1C or group 3, and received one intravenous infusion (group 1C) or three intravenous infusions (group 3, every two weeks) of each 3BNC117 and 10–1074. The combination of 3BNC117 and 10–1074 was more effective in suppressing viremia than either antibody alone. However, 3BNC117 and 10–1074 infusions failed to suppress viremia to undetectable levels in the two dual antibody-sensitive individuals with the highest pre-infusion viral load despite persistent reductions for up to 12 weeks.
Bar-On2018
(anti-idiotype, neutralization, immunotherapy, HAART, ART)
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10-1074: Chemoenzymatic synthesis, antigenicity, and immunogenicity of the V3 N334 glycopeptides from HIV-1 A244 gp120 have been reported. A synthetic V3 glycopeptide carrying a N334 high-mannose glycan was recognized by bNAb PGT128 and PGT126 but not by 10-1074. Rabbit immunization with the synthetic three-component A244 glycopeptide immunogen elicited substantial glycan-dependent antibodies with broad reactivity to various HIV-1 gp120/gp140 carrying N332 or N334 glycosylation sites. Switching the high- mannose glycan from N332 to N334 completely abolished binding of 10-1074.
Cai2018
(glycosylation, vaccine antigen design, structure)
-
10-1074: This study demonstrated that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens eliciting Ab responses with greater neutralization breadth. Data from four large virus panels were used to comprehensively map viral signatures associated with bNAb sensitivity, hypervariable region characteristics, and clade effects. The bNAb signatures defined for the V2 epitope region were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine which resulted in increased breadth of nAb responses compared with Env 459C alone. 10-1074 was used for analyzing clade sensitivity and extend further out, 671-683, NWFDISNWLWYIK with contacts including positions 671-673 and 676. 10-1074 was used for machine learning regression prediction and to analyze statistical details (Table S4)
Bricault2019
(antibody binding site, neutralization, vaccine antigen design, computational prediction, broad neutralizer)
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10–1074: In this phase 1b clinical trial, combination therapy with 3BNC117 and 10-1074 maintained suppression for between 15 and more than 30 weeks (median of 21 weeks) in nine out of 11 enrolled HIV-1 infected individuals. Subjects had been on ART until administration of combination therapy. None of the rebound viruses from pre-infusion latent reservoirs were resistant to both antibodies. Most were resistant to 10-1074 but still sensitive to 3BNC117.
Mendoza2018
(immunotherapy)
-
10-1074: In vitro neutralization data against 25 subtype A, 100 C, and 20 D pseudoviruses of 8 bNAbs (3BNC117, N6, VRC01, VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10–1074, PGT121) and 2 bispecific Abs under clinical development (10E8-iMAb, 3BNC117-PGT135) was studied to assess the antibodies’ potential to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. In vivo protection of these Abs and their 2-Ab combination was predicted using a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Conclusions were that 1. bNAb combinations outperform individual bNAbs 2. Different bNAb combinations were optimal against different HIV subtypes 3. Bispecific 10E8-iMAb outperformed all combinations, and 4. 10E8-iMAb in combination with other conventional Abs was predicted to be the best combination against HIV-infection.
Wagh2018
(neutralization, computational prediction, immunotherapy)
-
10-1074: A simple method to quantify and compare serum neutralization probabilities in described. The method uses logistic regression to model the probability that a serum neutralizes a virus with an ID50 titer above a cutoff. The neutralization potency (NP) identifies where the probabilities of neutralizing and not neutralizing a virus are equal and is not absolute as it depends on the ID50 cutoff. It provides a continuous measure for sera, which builds upon established tier categories now used to rate virus sensitivity. These potency comparisons are similar to comparing geometric mean neutralization titers, but instead are represented in tier-like terms. Increasing the number of bNAbs increases NP and slope, where the higher the slope, the sharper the boundary (lower scatter) between viruses neutralized and not neutralized. 10-1074 was used in analysis of monoclonal bNAb combinations.
Hraber2018
(assay or method development, neutralization)
-
10-1074: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. 10-1074 was isolated from human B cell clones and is functionally similar to super-Abs PGT121, PGT128 and PGT135. This is in Phase I clinical trial. Antigenic region V3 glycan (Table:1).
Walker2018
(antibody binding site, review, broad neutralizer)
-
10-1074: Polyreactive properties of natural and artificially engineered HIV-1 bNAbs were studied, with almost 60% of the tested HIV-1 bNAbs (including this one) exhibiting low to high polyreactivity in different immunoassays. A previously unappreciated polyreactive binding for PGT121, PGT128, NIH45-46W, m2, and m7 was reported. Binding affinity, thermodynamic, and molecular dynamics analyses revealed that the co-emergence of enhanced neutralizing capacities and polyreactivity was due to an intrinsic conformational flexibility of the antigen-binding sites of bNAbs, allowing a better accommodation of divergent HIV-1 Env variants.
Prigent2018
(antibody polyreactivity)
-
10-1074: This review discusses current HIV bNAb immunogen design strategies, recent progress made in the development of animal models to evaluate potential vaccine candidates, advances in the technology to analyze antibody responses, and emerging concepts in understanding B cell developmental pathways that may facilitate HIV vaccine design strategies.
Andrabi2018
(vaccine antigen design, review)
-
10-1074: A panel of bnAbs were studied to assess ongoing adaptation of the HIV-1 species to the humoral immunity of the human population. Resistance to neutralization is increasing over time, but concerns only the external glycoprotein gp120, not the MPER, suggesting a high selective pressure on gp120. Almost all the identified major neutralization epitopes of gp120 are affected by this antigenic drift, suggesting that gp120 as a whole has progressively evolved in less than 3 decades.
Bouvin-Pley2014
(neutralization)
-
10-1074: The first cryo-EM structure of a cross-linked vaccine antigen was solved. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a bNAb PGV04 Fab fragment revealed how cross-linking affects key properties of the trimer. SOSIP and GLA-SOSIP trimers were compared for antigenicity by ELISA, using a large panel of mAbs previously determined to react with BG505 Env. Non-NAbs globally lost reactivity (7-fold median loss of binding), likely because of covalent stabilization of the cross-linked ‘closed’ form of the GLA-SOSIP trimer that binds non-NAbs weakly or not at all. V3-specific non-NAbs showed 2.1–3.3-fold reduced binding. Three autologous rabbit monoclonal NAbs to the N241/N289 ‘glycan-hole’ surface, showed a median ˜1.5-fold reduction in binding. V3 non-NAb 4025 showed residual binding to the GLA-SOSIP trimer. By contrast, bNAbs like 10-1074 broadly retained reactivity significantly better than non-NAbs, with exception of PGT145 (3.3-5.3 fold loss of binding in ELISA and SPR).
Schiffner2018
(vaccine antigen design, binding affinity, structure)
-
10-1074: M428L and N434S mutations [referred to as “LS”] were introduced into the genes encoding the crystallizable fragment domains of 3BNC117 and 10-1074 bNAbs to increase their half-lives. The efficacy of modified bNAbs in blocking infections following repeated low dose mucosal challenges of rhesus macaques with the Tier 2 SHIVAD8-EO was evaluated. The most striking result was the long period of protective efficacy conferred by a single injection of crystallizable fragment domain-modified hbNAbs in macaques compared to that previously reported. A single intravenous infusion of the 10-1074-LS bNAb protected a cohort of 6 monkeys for up to 8.5 months (18 to 37 weeks). LS mutation in 10-1074 lengthened the median time until SHIVAD8-EO acquisition from 12.5 to 27 weeks, with 10-1074-LS bNAb measurable in the serum for 26 to 41 weeks and a calculated half-life of 3.8 weeks. The effects of the LS change on 3BNC117 were more modest than 10-1074, with a shorter half-life (2.6 versus 3.8 weeks), smaller increase in half-life (2 vs. 3.8-fold), and lower initial serum concentrations.
Gautam2018
(immunoprophylaxis)
-
10-1074: Panels of C clade pseudoviruses were computationally downselected from the panel of 200 C clade viruses defined by Rademeyer et al. 2016. A 12-virus panel was defined for the purpose of screening sera from vaccinees. Panels of 50 and 100 viruses were defined as smaller sets for use in testing magnitude and breadth against C clade. Published neutralization data for 16 mAbs was taken from CATNAP for the computational selections: 10-1074, 10-1074V, PGT121, PGT128, VRC26.25, VRC26.08, PGDM1400, PG9, PGT145, VRC07-523, 10E8, VRC13, 3BNC117, VRC07, VRC01, 4E10.
Hraber2017
(assay or method development, neutralization)
-
10-1074: Env from of a highly neutralization-resistant isolate, CH120.6, was shown to be very stable and conformationally-homogeneous. Its gp140 trimer retains many antigenic properties of the intact Env, while its monomeric gp120 exposes more epitopes. Thus trimer organization and stability are important determinants for occluding epitopes and conferring resistance to antibodies. Among a panel of 21 mAbs, CH120.6 was resistant to neutralization by all non-neutralizing and strain-specific mAbs, regardless of the location of their epitopes. It was weakly neutralized by several broadly-neutralizing mAbs (VRC01, NIH45-46, 12A12, PG9, PG16, PGT128, 4E10, and 10E8), and well neutralized by only 2 (PGT145 and 10-1074).
Cai2017
(neutralization)
-
10-1074: Mice twice-primed with DNA plasmids encoding HIV-1 gp120 and gag and given a double boost with HIV-1 virus-like particles (VLPs) i.e. DDVV immunization, elicited Env-specific antibody responses as well as Env- and Gag-specific CTL responses. In vivo electroporation (EP) was used to increase breadth and potency of response. Human anti-gp120 high mannose patch (centered on N137, N301, N332, N397) 10-1074 was used to prove that the VLP spike included the broad neutralization epitope recognized by it.
Huang2017a
(therapeutic vaccine, variant cross-reactivity)
-
10-1074: Early administration of bNAbs in a macaque-SHIV model is associated with a persistent very low level of viremia resulting in long-term infection control. Passive combination immunotherapy of 10-1074 and 3BNC117, 3 days after intrarectal infection, and targeting non-overlapping epitopes on the Env spike effected viremic suppression for 56-177 days, with rebound directly correlated to plasma concentration of bNAb.
Nishimura2017
(acute/early infection, immunotherapy)
-
10-1074: A panel of mAbs (2G12, VRC01, HJ16, 2F5, 4E10, 35O22, PG9, PGT121, PGT126, 10-1074) was tested to compare their efficacy in cell-free versus cell-cell transmission. Almost all bNAbs (with the exception of anti-CD4 mAb Leu3a) blocked cell-free infection with greater potency than cell-cell infection, and showed greater potency in neutralization of cell-free viruses. The lower effectiveness on neutralization was particularly pronounced for transmitted/founder viruses, and less pronounced for chronic and lab-adapted viruses. The study highlights that the ability of an antibody to inhibit cell-cell transmission may be an important consideration in the development of Abs for prophylaxis.
Li2017
(immunoprophylaxis, neutralization)
-
10-1074: This review focuses on the potential role of HIV-1-specific NAbs in preventing HIV-1 infection. Several NAbs have provided protection from infection in SHIV challenge studies in primates: b12, VRC01, VRC07-523LS, 3BNC117, PG9, PGT121, PGT126, 10-1074, 2G12, 4E10, 2F5, 10E8.
Pegu2017
(immunoprophylaxis, review)
-
10-1074: Crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation are presented, complexed with the V3-loop bNAb 10-1074 and IOMA, a new CD4bs bNAb. This is the first full description of the interplay between heterogeneous untrimmed high-mannose and complex-type N-glycans within the CD4bs and V3-loop epitopes, thereby revealing antibody-vulnerable glycan holes and roles of complex-type N-glycans on Env.
Gristick2016
(antibody binding site, glycosylation, structure)
-
10-1074: In 33 individuals (14 uninfected and 19 HIV-1-infected), intravenous infusion of 10-1074 was well tolerated. In infected individuals with sensitive strains, 10-1074 decreased viremia, but escape variants and viral rebound occurred within a few weeks. Escape variants were also resistant to V3 antibody PGT121, but remained sensitive to antibodies targeting other epitopes (3BNC117, VRC01 or PGDM1400). Loss of the PNGS at position N332 or 324G(D/N)IR327 mutation was associated with resistance to 10-1074 and PGT121.
Caskey2017
(escape, immunotherapy)
-
10-1074: This study assessed the ADCC activity of antibodies of varied binding types, including CD4bs (b6, b12, VRC01, PGV04, 3BNC117), V2 (PG9, PG16), V3 (PGT126, PGT121, 10-1074), oligomannose (2G12), MPER (2F5, 4E10, 10E8), CD4i (17b, X5), C1/C5 (A32, C11), cluster I (240D, F240), and cluster II (98-6, 126-7). ADCC activity was correlated with binding to Env on the surfaces of virus-infected cells. ADCC was correlated with neutralization, but not always for lab-adapted viruses such as HIV-1 NLA-3.
vonBredow2016
(effector function)
-
10-1074: This review summarizes representative anti-HIV MAbs of the first generation (2G12, b12, 2F5, 4E10) and second generation (PG9, PG16, PGT145, VRC26.09, PGDM1400, PGT121, PGT124, PGT128, PGT135, 10-1074, VRC01, 3BNC117, CH103, PGT151, 35O22, 8ANC195, 10E8). Structures, epitopes, VDJ usage, CDR usage, and degree of somatic hypermutation are compared among these antibodies. The use of SOSIP trimers as immunogens to elicit B-cell responses is discussed.
Burton2016
(review, structure)
-
10-1074: Two stable homogenous gp140 Env trimer spikes, Clade A 92UG037.8 Env and Clade C C97ZA012 Env, were identified. 293T cells stably transfected with either presented fully functional surface timers, 50% of which were uncleaved. A panel of neutralizing and non-neutralizing Abs were tested for binding to the trimers. V3 glycan bNAb 10-1074 bound cell surface tightly whether the trimer contained its C-terminal or not, and was competed out by sCD4. It was able to neutralize the 92UG037.8 HIV-1 isolate weakly.
Chen2015
(neutralization, binding affinity)
-
10-1074: This review discusses the application of bNAbs for HIV treatment and eradication, focusing on bnAbs that target key epitopes, specifically: 2G12, 2F5, 4E10, VRC01, 3BNC117, PGT121, VRC26.08, VRC26.09, PGDM1400, and 10-1074. Antibody 10-1074 was included in an early trial of combination therapies, administered together with 3BNC117 and PG16 in mice.
Stephenson2016
(immunotherapy, review)
-
10-1074: This review discusses an array of methods to engineer more effective bNAbs for immunotherapy. Antibody 10-1074 is an example of engineering through rational mutations; it has been combined with PGT121 as part of a strategy to combine the CDRs of bnAbs targeting similar epitopes.
Hua2016
(immunotherapy, review)
-
10-1074: This study examined the neutralization of group N, O, and P primary isolates of HIV-1 by diverse antibodies. Cross-group neutralization was observed only with the bNAbs targeting the N160 glycan-V1/V2 site. Four group O isolates, 1 group N isolate, and the group P isolates were neutralized by PG9 and/or PG16 or PGT145 at low concentrations. None of the non-M primary isolates were neutralized by bNAbs targeting other regions, except 10E8, which weakly neutralized 2 group N isolates, and 35O22 which neutralized 1 group O isolate. Bispecific bNAbs (PG9-iMab and PG16-iMab) very efficiently neutralized all non-M isolates with IC50 below 1 ug/mL, except for 2 group O strains. Anti-V3 bNAb 10-1074 was able to neutralize only 1/16 tested non-M primary isolates at an IC50< 10µg/ml, RBF208,M/O at 2.86 µg/ml.
Morgand2015
(neutralization, subtype comparisons)
-
10-1074: The neutralization of 14 bnAbs was assayed against a global panel of 12 or 17 Env pseudoviruses. From IC50, IC80, IC90, and IC99 values, the slope of the dose-response curve was calculated. Each class of Ab had a fairly consistent slope. Neutralization breadth was strongly correlated with slope. An IIP (Instantaneous Inhibitory Potential) value was calculated, based on both the slope and IC50, and this value may be predictive of clinical efficacy. 10-1074, a V3-glycan bnAb belonged to a group with slopes >1.
Webb2015
(neutralization)
-
10-1074: The dynamics and characteristics of anti-antibody responses were described for monkeys that received adenovirus-mediated delivery of either rhesus anti-SIV antibody constructs (4L6 or 5L7) in prevention trials, or a combination of rhesusized human anti-HIV antibodies (1NC9/8ANC195/3BNC117 or 10-1074/10E8/3BNC117) in therapy trials. Anti-antibody responses to the human mAbs were correlated to the distance from the germline Ab sequences.
Martinez-Navio2016
(immunotherapy)
-
10-1074: Based on the results of 3BNC117 administered to human subjects, mathematical modeling was unable to recapitulate the kinetics of the viral decline. Revision of the model to fit the data suggested that the antibody may clear infected cells, in addition to neutralizing free virions. In in vitro experiments, 3BNC177, PG16, and 10-1074 were able to stain cells infected with HIV-1 YU2. Both 3BNC117 and 10-1074 recognized cells infected with primary virus isolates from human subjects that had been previously infused with 3BNC117. Either 3BNC117 alone, or in combination with 10-1074, was able to accelerate the clearance of YU2-infected cells in humanized mice, decreasing the half life of the infected cell. This result was shown to be mediated by the Fc-gamma receptor.
Lu2016
(effector function, immunotherapy)
-
10-1074: A panel of antibodies was tested for binding, stability, and ADCC activity on HIV-infected cells. The differences in killing efficiency were linked to changes in binding of the antibody and the accessibility of the Fc region when bound to infected cells. Ab 10-1074 had strong ADCC.
Bruel2016
(effector function, binding affinity)
-
10-1074: This review summarized bNAb immunotherapy studies. Several bnAbs have been shown to decrease viremia in vivo, and are a prospect for preventative vaccinations. bNAbs have 3 possible immune effector functions: (1) directly neutralizing virions, (2) mediating anti-viral activity through Fc-FcR interactions, and (3) binding to viral antigen to be taken up by dendritic cells. In contrast to anti-HIV mAbs, antibodies against host cell CD4 and CCR5 receptors (iMab and PRO 140) are hindered by their short half-life in vivo. MAb 10-1074 has been associated with viral suppression in studies of humanized mice and rhesus macaques.
Halper-Stromberg2016
(immunotherapy, review)
-
10-1074: Four bNAbs (VRC01, VRC01-LS, 3BNC117, and 10-1074) were administered, singly or in combination, to macaques, followed by weekly challenges with clade B SHIVAD8. In all cases, the administration of MAbs delayed virus acquisition. Control animals required 2 to 6 challenges before becoming infected, while animals receiving VRC01 required 4–12 challenges; 3BNC117 required 7–20 challenges; 10-1074 required 6–23 challenges; and VRC01-LS required 9–18 challenges. Animals that received a single antibody infusion resisted infection for up to 23 weekly challenges.
Gautam2016
(immunotherapy)
-
10-1074: Double, triple or quadruple combinations of fifteen bNAbs that target 4 distinct epitope regions: the CD4 binding site (3BNC117, VRC01, VRC07, VRC07-523, VRC13), the V3-glycan supersite (10–1074, 10-1074V, PGT121, PGT128), the V1/V2-glycan site (PG9, PGT145, PGDM1400, CAP256-VRC26.08, CAP256-VRC26.25), and the gp41 MPER epitope (10E8) were studied. Their neutralization potency and breadth were assayed against a panel of 200 acute/early subtype C strains, and compared to a novel, highly accurate predictive mathematical model (no-overlap Bliss Hill model, CombiNaber tool, LANL HIV Immunology database). These data were used to predict the best combinations of bNAbs for immunotherapy.
Wagh2016
(neutralization, immunotherapy)
-
10-1074: A subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4+ lymphocytes have been identified. These antibodies target either the CD4-binding site or the glycan/V3 loop on HIV-1 gp120 and act at low concentrations by inhibiting multiple steps of viral cell to cell transmission. This property of blocking viral cell to cell transmission to plasmacytoid DCs and interfering with type-I IFN production should be considered an important characteristic defining the potency for therapeutic or prophylactic antiviral strategies. 10-1074 was active against cell to cell transmission of T/F viruses.
Malbec2013
-
10-1074: 10-1074 in combination with NAbs NH45-46m2 and NIH46-42m7 was able to control viremia as well as to reduce routes to escape of YU-2 HIV-1.
Diskin2013
(enhancing activity)
-
10-1074: This is a review of a satellite symposium at the AIDS Vaccine 2012 conference, focusing on antibody gene transfer. Michel Nussenzweig presented studies exploring the possibility that antibodies might also be used to treat established infections. They found that combinations of five broadly neutralizing antibodies NIH45-46G54W, PG16, PGT128, 10-1074 and 3BC176 MAbs, controlled HIV-1 infection and suppressed the viral load to below the limit of detection during the entire therapy period of up to 60 days.
Balazs2013
(immunoprophylaxis, immunotherapy)
-
10-1074: A computational tool (Antibody Database) identifying Env residues affecting antibody activity was developed. As input, the tool incorporates antibody neutralization data from large published pseudovirus panels, corresponding viral sequence data and available structural information. The model consists of a set of rules that provide an estimated IC50 based on Env sequence data, and important residues are found by minimizing the difference between logarithms of actual and estimated IC50. The program was validated by analysis of MAb 8ANC195, which had unknown specificity. Predicted critical N-glycosylation for 8ANC195 were confirmed in vitro and in humanized mice. The key associated residues for each MAb are summarized in the Table 1 of the paper and also in the Neutralizing Antibody Contexts & Features tool at Los Alamos Immunology Database.
West2013
(glycosylation, computational prediction)
-
10-1074: Somatic hypermutations are preferably found in CDR loops, which alter the Ab combining sites, but not the overall structure of the variable domain. FWR of CDR are usually resistant to and less tolerant of mutations. This study reports that most bnAbs require somatic mutations in the FWRs which provide flexibility, increasing Ab breadth and potency. To determine the consequence of FWR mutations the framework residues were reverted to the Ab's germline counterpart (FWR-GL) and binding and neutralizing properties were then evaluated. 10-1074, which recognizes the base of the V3 loop, was among the 17 bnAbs which were used in studying the mutations in FWR.
Klein2013
(neutralization, structure, antibody lineage)
-
10-1074: HIV therapy by combinations of 5 bNAbs was tested in YU2-infected humanized mice. Penta-mix (PG16, 45-46W, 3BC176, PGT128 and 10-1074) was the most effective in controlling viraemia compared to tri-mix (PG16, 45-46, 3BC176) and monotherapy (Fig S9). Viral escape with 10-1074 monotherapy was associated with mutations at residues 332 or 334, both of which abrogate the same potential N-linked glycosylation site in V1/V2 loop.
Klein2012a
(escape, immunotherapy)
-
10-1074: Several antibodies including 10-1074 were isolated from B-cell clone encoding PGT121, from a clade A-infected African donor using YU-2 gp140 trimers as bait. These antibodies were segregated into PGT121-like (PGT121-123 and 9 members) and 10-1074-like (20 members) groups distinguished by sequence, binding affinity, carbohydrate recognition, neutralizing activity, the V3 loop binding and the role of glycans in epitope formation. The epitopes for both groups contain a potential N-linked glycosylation site (PNGS) at Asn332gp120 and the base of the V3 loop of the gp120 subunit of the HIV spike. However, the 10-1074–like Abs required an intact PNGS at Asn332gp120 for their neutralizing activity, whereas PGT121-like antibodies were able to neutralize some viral strains lacking the Asn332gp120 PNGS. All PGT121 variant antibodies neutralized 9 pseudoviruses and didn't neutralize the r1166.cl control lacking PNGS at gp120 position 332. Group 10-1074 exhibited remarkable potency and breadth, but no detectable binding to protein-free glycans. Crystal structures of unliganded PGT121 and 10-1074 were compared and revealed differential carbohydrate recognition maps to a cleft between (CDR)H2 and CDRH3, occupied by a complex-type N-glycan. Detail information on the binding and neutralization assays are described in the figures S2-S11.
Mouquet2012a
(antibody generation, glycosylation, neutralization, binding affinity, structure, broad neutralizer)
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Stefic2019
Karl Stefic, Mélanie Bouvin-Pley, Asma Essat, Clara Visdeloup, Alain Moreau, Cécile Goujard, Marie-Laure Chaix, Martine Braibant, Laurence Meyer, and Francis Barin. Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02\_AG Viruses with a Focus on Evolution over Time. J. Virol., 93(2), 15 Jan 2019. PubMed ID: 30404804.
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Stephenson2016
Kathryn E. Stephenson and Dan H. Barouch. Broadly Neutralizing Antibodies for HIV Eradication. Curr. HIV/AIDS Rep., 13(1):31-37, Feb 2016. PubMed ID: 26841901.
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Stephenson2021
Kathryn E. Stephenson, Boris Julg, C. Sabrina Tan, Rebecca Zash, Stephen R. Walsh, Charlotte-Paige Rolle, Ana N. Monczor, Sofia Lupo, Huub C. Gelderblom, Jessica L. Ansel, Diane G. Kanjilal, Lori F. Maxfield, Joseph Nkolola, Erica N. Borducchi, Peter Abbink, Jinyan Liu, Lauren Peter, Abishek Chandrashekar, Ramya Nityanandam, Zijin Lin, Alessandra Setaro, Joseph Sapiente, Zhilin Chen, Lisa Sunner, Tyler Cassidy, Chelsey Bennett, Alicia Sato, Bryan Mayer, Alan S. Perelson, Allan deCamp, Frances H. Priddy, Kshitij Wagh, Elena E. Giorgi, Nicole L. Yates, Roberto C. Arduino, Edwin DeJesus, Georgia D. Tomaras, Michael S. Seaman, Bette Korber, and Dan H. Barouch. Safety, Pharmacokinetics and Antiviral Activity of PGT121, a Broadly Neutralizing Monoclonal Antibody Against HIV-1: A Randomized, Placebo-Controlled, Phase 1 Clinical Trial. Nat. Med., 27(10):1718-1724, Oct 2021. PubMed ID: 34621054.
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Vanshylla2021
Kanika Vanshylla, Kathrin Held, Tabea M Eser, Henning Gruell, Franziska Kleipass, Ricarda Stumpf, Kanika Jain, Daniela Weiland, Jan Münch, Berthold Grüttner, Christof Geldmacher, and Florian Klein. CD34T+ Humanized Mouse Model to Study Mucosal HIV-1 Transmission and Prevention. Vaccines, 9(3), 27 Feb 2021. PubMed ID: 33673566.
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vonBredow2016
Benjamin von Bredow, Juan F. Arias, Lisa N. Heyer, Brian Moldt, Khoa Le, James E. Robinson, Susan Zolla-Pazner, Dennis R. Burton, and David T. Evans. Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies. J. Virol., 90(13):6127-6139, 1 Jul 2016. PubMed ID: 27122574.
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Wagh2016
Kshitij Wagh, Tanmoy Bhattacharya, Carolyn Williamson, Alex Robles, Madeleine Bayne, Jetta Garrity, Michael Rist, Cecilia Rademeyer, Hyejin Yoon, Alan Lapedes, Hongmei Gao, Kelli Greene, Mark K. Louder, Rui Kong, Salim Abdool Karim, Dennis R. Burton, Dan H. Barouch, Michel C. Nussenzweig, John R. Mascola, Lynn Morris, David C. Montefiori, Bette Korber, and Michael S. Seaman. Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection. PLoS Pathog., 12(3):e1005520, Mar 2016. PubMed ID: 27028935.
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Wagh2018
Kshitij Wagh, Michael S. Seaman, Marshall Zingg, Tomas Fitzsimons, Dan H. Barouch, Dennis R. Burton, Mark Connors, David D. Ho, John R. Mascola, Michel C. Nussenzweig, Jeffrey Ravetch, Rajeev Gautam, Malcolm A. Martin, David C. Montefiori, and Bette Korber. Potential of Conventional \& Bispecific Broadly Neutralizing Antibodies for Prevention of HIV-1 Subtype A, C \& D Infections. PLoS Pathog., 14(3):e1006860, Mar 2018. PubMed ID: 29505593.
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Walker2018
Laura M. Walker and Dennis R. Burton. Passive Immunotherapy of Viral Infections: `Super-Antibodies' Enter the Fray. Nat. Rev. Immunol., 18(5):297-308, May 2018. PubMed ID: 29379211.
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Wang2018a
Hongye Wang, Ting Yuan, Tingting Li, Yanpeng Li, Feng Qian, Chuanwu Zhu, Shujia Liang, Daniel Hoffmann, Ulf Dittmer, Binlian Sun, and Rongge Yang. Evaluation of Susceptibility of HIV-1 CRF01\_AE Variants to Neutralization by a Panel of Broadly Neutralizing Antibodies. Arch. Virol., 163(12):3303-3315, Dec 2018. PubMed ID: 30196320.
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Wang2019
Qian Wang, Lihong Liu, Wuze Ren, Agegnehu Gettie, Hua Wang, Qingtai Liang, Xuanling Shi, David C. Montefiori, Tongqing Zhou, and Linqi Zhang. A Single Substitution in gp41 Modulates the Neutralization Profile of SHIV during In Vivo Adaptation. Cell Rep., 27(9):2593-2607.e5, 28 May 2019. PubMed ID: 31141685.
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Wang2020
Zijun Wang, Christopher O. Barnes, Rajeev Gautam, Julio C. Cetrulo Lorenzi, Christian T. Mayer, Thiago Y. Oliveira, Victor Ramos, Melissa Cipolla, Kristie M. Gordon, Harry B. Gristick, Anthony P. West, Yoshiaki Nishimura, Henna Raina, Michael S. Seaman, Anna Gazumyan, Malcolm Martin, Pamela J. Bjorkman, Michel C. Nussenzweig, and Amelia Escolano. A Broadly Neutralizing Macaque Monoclonal Antibody against the HIV-1 V3-Glycan Patch. eLife, 9, 21 Oct 2020. PubMed ID: 33084569.
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Ward2019
Andrew B. Ward. Playing Chess with HIV. Immunity, 50(2):283-285 doi, Feb 2019. PubMed ID: 30784575
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Webb2015
Nicholas E. Webb, David C. Montefiori, and Benhur Lee. Dose-Response Curve Slope Helps Predict Therapeutic Potency and Breadth of HIV Broadly Neutralizing Antibodies. Nat. Commun., 6:8443, 29 Sep 2015. PubMed ID: 26416571.
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West2013
Anthony P. West, Jr., Louise Scharf, Joshua Horwitz, Florian Klein, Michel C. Nussenzweig, and Pamela J. Bjorkman. Computational Analysis of Anti-HIV-1 Antibody Neutralization Panel Data to Identify Potential Functional Epitope Residues. Proc. Natl. Acad. Sci. U.S.A., 110(26):10598-10603, 25 Jun 2013. PubMed ID: 23754383.
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Wieczorek2023
Lindsay Wieczorek, Eric Sanders-Buell, Michelle Zemil, Eric Lewitus, Erin Kavusak, Jonah Heller, Sebastian Molnar, Mekhala Rao, Gabriel Smith, Meera Bose, Amy Nguyen, Adwitiya Dhungana, Katherine Okada, Kelly Parisi, Daniel Silas, Bonnie Slike, Anuradha Ganesan, Jason Okulicz, Tahaniyat Lalani, Brian K. Agan, Trevor A. Crowell, Janice Darden, Morgane Rolland, Sandhya Vasan, Julie Ake, Shelly J. Krebs, Sheila Peel, Sodsai Tovanabutra, and Victoria R. Polonis. Evolution of HIV-1 envelope towards reduced neutralization sensitivity, as demonstrated by contemporary HIV-1 subtype B from the United States. PLoS Pathog, 19(12):e1011780 doi, Dec 2023. PubMed ID: 38055771
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Wilson2021
Andrew Wilson, Leyn Shakhtour, Adam Ward, Yanqin Ren, Melina Recarey, Eva Stevenson, Maria Korom, Colin Kovacs, Erika Benko, R. Brad Jones, and Rebecca M. Lynch. Characterizing the Relationship between Neutralization Sensitivity and env Gene Diversity During ART Suppression. Front. Immunol., 12:710327, 15 Sep 2021. PubMed ID: 34603284.
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Yang2022
Zhi Yang, Kim-Marie A. Dam, Michael D. Bridges, Magnus A. G. Hoffmann, Andrew T. DeLaitsch, Harry B. Gristick, Amelia Escolano, Rajeev Gautam, Malcolm A. Martin, Michel C. Nussenzweig, Wayne L. Hubbell, and Pamela J. Bjorkman. Neutralizing Antibodies Induced in Immunized Macaques Recognize the CD4-Binding Site on an Occluded-Open HIV-1 Envelope Trimer. Nat. Commun., 13(1):732, 8 Feb 2022. PubMed ID: 35136084.
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Zhang2022
Baoshan Zhang, Deepika Gollapudi, Jason Gorman, Sijy O'Dell, Leland F. Damron, Krisha McKee, Mangaiarkarasi Asokan, Eun Sung Yang, Amarendra Pegu, Bob C. Lin, Cara W. Chao, Xuejun Chen, Lucio Gama, Vera B. Ivleva, William H. Law, Cuiping Liu, Mark K. Louder, Stephen D. Schmidt, Chen-Hsiang Shen, Wei Shi, Judith A. Stein, Michael S. Seaman, Adrian B. McDermott, Kevin Carlton, John R. Mascola, Peter D. Kwong, Q. Paula Lei, and Nicole A. Doria-Rose. Engineering of HIV-1 Neutralizing Antibody CAP256V2LS for Manufacturability and Improved Half Life. Sci. Rep., 12(1):17876, 25 Oct 2022. PubMed ID: 36284200.
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