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Displaying record number 872

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MAb ID	Fab D5 (D5)
HXB2 Location	Env	Env Epitope Map
Author Location	gp41( LAI)
Epitope
Subtype	B
Ab Type	gp41 cluster II
Neutralizing
Species (Isotype)	human(IgG1κ)
Patient	D
Immunogen	HIV-1 infection
Keywords	ADCC, antibody binding site, antibody interactions, antibody lineage, antibody sequence, assay or method development, binding affinity, kinetics, mimics, neutralization, review, structure, subtype comparisons, vaccine antigen design, vaccine-induced immune responses, variant cross-reactivity

Notes

Showing 22 of 22 notes.

Fab D5: Isolation of human mAb, E10, from an HIV-1-infected patient sample by single B cell sorting and single cell PCR has been reported. E10 showed binding to gp140 trimer and linear peptides derived from gp41 membrane proximal external region (MPER). IgG E10 use a famous V gene segment IGHV1-69 allelic variants including Fab D5. Antibodies derived from this germline V gene tend to have a hydrophobic CDR2 and bind to hydrophobic alpha helix rich portions. Fine mapping of E10 epitope may potentiate MPER-based subunit vaccine development. Yang2018 (ADCC)
D5: 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. D5 was used in comparing the Ab framework amino acid replacement vs. interactive surface area on Ab. Klein2013 (neutralization, structure, antibody lineage)
D5: The rational design of vaccines to elicit broadly neutralizing antibodies to HIV-1 is discussed in relation to understanding of vaccine recognition sites, the structural basis of interaction with HIV-1 env and vaccine developmental pathways. D5 has been mentioned as an antibody of low potency and limited breadth of neutralization as it recognizes N-heptad repeats of GP41. Kwong2011 (antibody binding site, neutralization, vaccine antigen design, review)
D5: The capacity of D5 to block completely the activity of the anti-HIV peptide T20 was investigated. T20 inhibited the fusion or syncytia formation between co-cultured CHO-WT cells expressing HIV-1 HXB2 envelope glycoprotein on their surface and HeLaT4 cells. D5 was not able to block the anti-fusion effect of T20 Vincent2012 (antibody interactions)
Fab D5: Molecular dynamics simulation was used to provide the dynamic binding picture for HK20 and D5 MAbs. Alanine scanning at protein-protein interface revealed that the highest contributors to binding for D5 Fab are F54 of V(H) region and W32 and Y94 of V(L) region. D5 I52, F54, and T56, bind to the gp41 hydrophobic binding pocket, an important region targeted by many other fusion inhibitors. Hydrogen bonding analysis also identified high-occupancy hydrogen bonds at the periphery of gp41 hydrophobic pocket. Hartono2012 (binding affinity)
Fab D5: Characteristics of patients' plasma and their respective mAbs in multiple neutralization assay formats was presented. HK20 MAb neutralized SF162 (B) and 92Br025 (C) isolates against a panel of 17 primary viruses belonging to 6 subtypes in the 24/1/14 extended incubation PBMC assay. In another experiment, out of the 12 isolates, HK20 MAb neutralized three in 24/1/14 PBMC assays, one in 1/2/7 PBMC assays, one in 1/24/14 PBMC assays, none in TZMbl_IV assays, one in TZMbl_PV assays and one in GHOST_PV assays. When evaluating plasma vs. Ab in the TZMbl pseudovirus assay, HK20 MAb neutralized one out of three Tier 1 strains and one out of eleven Tier 2 strains. Balla-Jhagjhoorsingh2011 (neutralization, subtype comparisons)
D5: This review discusses current understanding of Env neutralization by antibodies in relation to epitope exposure and how this insight might benefit vaccine design strategies. This MAb is in the list of current MAbs with notable cross-neutralizing activity. Pantophlet2010 (neutralization, variant cross-reactivity, review)
D5: D5 was shown to capture virion particles completely devoid of HIV-1 Env. Virus capture assay was modified with added incubation of virions and MAbs in solution followed by removal of unbound MAbs, which nearly eliminated the Env-independent binding by this Ab. Leaman2010 (assay or method development)
D5: Potential small molecule vaccine mimetics of the NHR trimer in gp41 (hapten immunogenic) were discovered and optimized to induce D5-like antibody response in mice. Binding of prepared hapten compounds to D5 was confirmed by SPR. A carrier protein was conjugated with the haptens to provide antibody epitopes to helper T cells. Very high titered antibodies were elicited by hapten-carrier conjugates compared to individual self-haptens. And, the antisera cross-reacted strongly to each heterologous hapten. Another experiment was conducted to determine if D5-like antibody response was induced during the course of natural HIV-1 infection and the results suggested the presence of D5-like antibodies. mAbs 1b12, 2F5, 2G12, 4E10, PG9 or P16 might be better targets for additional HTS experiments. Caulfield2010 (vaccine antigen design, kinetics, binding affinity)
D5: Optimized peptide mimetics of gp41 prehairpin intermediates were constructed to induce neutralizing responses in vaccinated guinea pigs and rabbits. Neutralization potency of sera from animals immunized with covalent trimeric immunogens was greater than the potency of sera from animals immunized with noncovalent trimers. Sera from animals immunized with longer constructs was more neutralizing and contained higher concentration of D5-like Abs compared to antisera from shorter constructs. Sera from immunized guinea pigs, but not from rabbits, neutralized half of the Tier 1 viruses tested. For the analyses, a mutant virus (HXB2-V570A) was used, which is hypersensitive to Abs binding to the pre-hairpin intermediate but not to mAbs that bind elsewhere. This was supported by neutralization analyses with D5, where this Ab neutralized HXB2-V570A virus more potently than the HXB2 wild type. Bianchi2010 (mimics, neutralization, vaccine-induced immune responses)
D5: Affinity interactions between D5 scFv and 5-Helix were studied using combinatorial alanine scanning mutagenesis of the D5 light chain CDR residues. A cluster of hotspot residues at the Vh-Vl interface (Y94, P95, L96) was found to contribute significantly to the high affinity interaction between the Ab and the 5-Helix. In addition, a residue at the periphery of the combining site on LCDR1, Y30, was also found to play a role in the high affinity interaction. DaSilva2010 (binding affinity)
D5: Crystal structure of D5 was compared to the crystal structure of HK20 in complex with gp41 5-Helix. HK20 employed two CDR loops to contact gp41, while D5 utilized all 6 CDRs. The affinity and kinetics of HK20 and D5 were similar. In TZM-based assay, D5 neutralized only one isolate, while HK20 neutralized 4/18 HIV isolates. In the HOS-based assay, D5 neutralized 11/18 HIV isolates, while HK20 neutralized all 18 isolates. Sabin2010 (neutralization, variant cross-reactivity, kinetics, binding affinity)
D5: Crystal structure of D5 was compared to crystal structures of the non-neutralizing 8062 and broadly neutralizing 8066 MAbs in complex with 5-Helix. For all three Abs, binding affinity correlated with neutralization activity. Structural modeling analyses revealed relatively small differences in the interactions of 8062 and 8066 with the antigen compared to D5, showing a remarkable convergence in the optimal sequence and conformation of the CDR-H2 loop. Gustchina2010 (structure)
D5: D5 drug-mimicry mode of epitope recognition is reviewed in detail. The review also summarizes on how different modes of Ab binding and recognition are used to overcome viral evasion tactics and how this knowledge may be used to re-elicit responses in vivo. Kwong2009a (antibody binding site, review)
D5: The crystal structure for VRC01 in complex with an HIV-1 gp120 core from a clade A/E recombinant strain was analyzed to understand the structural basis for its neutralization breadth and potency. The number of mutations from the germline and the number of mutated contact residues for D5 were smaller than those for VRC01. Zhou2010 (neutralization, structure)
D5: This review provides information on the HIV-1 glycoprotein properties that make it challenging to target with neutralizing Abs. D5 neutralization properties and binding to HIV-1 envelope, and current strategies to develop versions of the Env spike with functional trimer properties for elicitation of broadly neutralizing Abs, are discussed. In addition, approaches to target cellular molecules, such as CD4, CCR5, CXCR4, and MHC molecules, with therapeutic Abs are reviewed. Phogat2007 (review)
D5: D5 structure, binding, neutralization, and strategies that can be used for vaccine antigen design to elicit anti-gp41 Abs, are reviewed in detail. Lin2007 (review)
D5: Synergy of 2F5 with MAbs 2G12, D5, and peptide C34 was examined. 2F5 exhibited synergy in inhibition of HIV-1 89.6 with MAb 2G12, D5 and peptide C34. In combination with a matured D5 variant (2-75), the synergistic effect was increased. D5 and 2F5 contributed equally to the observed synergy. It is suggested that 2F5 and D5 have complementary roles, binding to distinct but adjacent Env trimers on the same virion, thereby synergistically preventing formation of fusion pores. Hrin2008 (antibody interactions)
D5: D5 scFv and D5 IgG, along with C-peptide inhibitors of different sizes, were used to determine if the pocket region of the gp41 N-trimer is specifically protected by a steric block. The smaller D5 scFv was 4 times more potent than the larger D5 IgG in inhibiting HIV entry. In contrast, in an in vitro binding assay, 5-10 fold more IgG than scFv bound to target. This disparity indicates that there is a steric block at the pocket region. N-trimer was shown to be sterically protected from inhibitors and NAbs approaching from both the cell side and the virus side, and that the N-trimer block is present also on a CD4-activated virus. It is suggested that the source of the steric block is derived from viral factors, such as gp120. Eckert2008 (antibody binding site)
D5: The potency of D5 was 2-3 times lower than the potency of new neutralizing Fab 3674 in neutralization of laboratory and primary strains of HIV-1. Gustchina2007 (neutralization)
Fab D5: Called D5. One of 19 MAbs and Fabs in this database that bind to the highly immunogenic gp41 cluster II region (aa 644-663); none have neutralizing activity. Gorny2003 (review)
Fab D5: Binds to cluster II region -- competes with MAbs 126-6, Md-1 and D50 -- conformation sensitive -- variable regions sequenced. Binley1996 (antibody binding site, antibody sequence)

References

Showing 22 of 22 references.

Isolation Paper
Binley1996 J. M. Binley, H. J. Ditzel, C. F. Barbas III, N. Sullivan, J. Sodroski, P. W. H. I. Parren, and D. R. Burton. Human Antibody Responses to HIV Type 1 Glycoprotein 41 Cloned in Phage Display Libraries Suggest Three Major Epitopes Are Recognized and Give Evidence for Conserved Antibody Motifs in Antigen Binding. AIDS Res. Hum. Retroviruses, 12:911-924, 1996. A panel of anti-gp41 human Fab fragments were generated by panning phage display antibody libraries prepared from HIV-1 positive donors with rgp41. Fabs tended to be directed against three epitopes, designated clusters I-III. None were neutralizing. A common CDR3 motif was found in several of the heavy chain sequences. PubMed ID: 8798976. Show all entries for this paper.

Balla-Jhagjhoorsingh2011 Sunita S. Balla-Jhagjhoorsingh, Betty Willems, Liesbeth Heyndrickx, Leo Heyndrickx, Katleen Vereecken, Wouter Janssens, Michael S. Seaman, Davide Corti, Antonio Lanzavecchia, David Davis, and Guido Vanham. Characterization of Neutralizing Profiles in HIV-1 Infected Patients from Whom the HJ16, HGN194 and HK20 mAbs Were Obtained. PLoS One, 6(10):e25488, 2011. PubMed ID: 22016769. Show all entries for this paper.

Bianchi2010 Elisabetta Bianchi, Joseph G. Joyce, Michael D. Miller, Adam C. Finnefrock, Xiaoping Liang, Marco Finotto, Paolo Ingallinella, Philip McKenna, Michael Citron, Elizabeth Ottinger, Robert W. Hepler, Renee Hrin, Deborah Nahas, Chengwei Wu, David Montefiori, John W. Shiver, Antonello Pessi, and Peter S. Kim. Vaccination with Peptide Mimetics of the gp41 Prehairpin Fusion Intermediate Yields Neutralizing Antisera against HIV-1 Isolates. Proc. Natl. Acad. Sci. U.S.A., 107(23):10655-10660, 8 Jun 2010. PubMed ID: 20483992. Show all entries for this paper.

Caulfield2010 Michael J. Caulfield, Vadim Y. Dudkin, Elizabeth A. Ottinger, Krista L. Getty, Paul D. Zuck, Robin M. Kaufhold, Robert W. Hepler, Georgia B. McGaughey, Michael Citron, Renee C. Hrin, Ying-Jie Wang, Michael D. Miller, and Joseph G. Joyce. Small Molecule Mimetics of an HIV-1 gp41 Fusion Intermediate As Vaccine Leads. J. Biol. Chem., 285(52):40604-40611, 24 Dec 2010. PubMed ID: 20943652. Show all entries for this paper.

DaSilva2010 Gustavo F. Da Silva, Joseph S. Harrison, and Jonathan R. Lai. Contribution of Light Chain Residues to High Affinity Binding in an HIV-1 Antibody Explored by Combinatorial Scanning Mutagenesis. Biochemistry, 49(26):5464-5472, 6 Jul 2010. PubMed ID: 20518570. Show all entries for this paper.

Eckert2008 Debra M. Eckert, Yu Shi, Sunghwan Kim, Brett D. Welch, Eunchai Kang, Emily S. Poff, and Michael S. Kay. Characterization of the Steric Defense of the HIV-1 gp41 N-Trimer Region. Protein Sci., 17(12):2091-2100, Dec 2008. PubMed ID: 18802030. Show all entries for this paper.

Gorny2003 Miroslaw K. Gorny and Susan Zolla-Pazner. Human Monoclonal Antibodies that Neutralize HIV-1. In Bette T. M. Korber and et. al., editors, HIV Immunology and HIV/SIV Vaccine Databases 2003. pages 37--51. Los Alamos National Laboratory, Theoretical Biology \& Biophysics, Los Alamos, N.M., 2004. URL: http://www.hiv.lanl.gov/content/immunology/pdf/2003/zolla-pazner_article.pdf. LA-UR 04-8162. Show all entries for this paper.

Gustchina2007 Elena Gustchina, John M. Louis, Son N. Lam, Carole A. Bewley, and G. Marius Clore. A Monoclonal Fab Derived from a Human Nonimmune Phage Library Reveals a New Epitope on gp41 and Neutralizes Diverse Human Immunodeficiency Virus Type 1 Strains. J. Virol., 81(23):12946-12953, Dec 2007. PubMed ID: 17898046. Show all entries for this paper.

Gustchina2010 Elena Gustchina, Mi Li, John M. Louis, D. Eric Anderson, John Lloyd, Christian Frisch, Carole A. Bewley, Alla Gustchina, Alexander Wlodawer, and G. Marius Clore. Structural Basis of HIV-1 Neutralization by Affinity Matured Fabs Directed against the Internal Trimeric Coiled-Coil of gp41. PLoS Pathog., 6(11):e1001182, 2010. PubMed ID: 21085615. Show all entries for this paper.

Hartono2012 Yossa Dwi Hartono, Raudah Lazim, Yew Mun Yip, and Dawei Zhang. Computational Study of Bindings of HK20 Fab and D5 Fab to HIV-1 gp41. Bioorg. Med. Chem. Lett., 22(4):1695-1700, 15 Feb 2012. PubMed ID: 22260771. Show all entries for this paper.

Hrin2008 Renee Hrin, Donna L. Montgomery, Fubao Wang, Jon H. Condra, Zhiqiang An, William R. Strohl, Elisabetta Bianchi, Antonello Pessi, Joseph G. Joyce, and Ying-Jie Wang. Short Communication: In Vitro Synergy between Peptides or Neutralizing Antibodies Targeting the N- and C-Terminal Heptad Repeats of HIV Type 1 gp41. AIDS Res. Hum. Retroviruses, 24(12):1537-1544, Dec 2008. PubMed ID: 19102685. Show all entries for this paper.

Klein2013 Florian Klein, Ron Diskin, Johannes F. Scheid, Christian Gaebler, Hugo Mouquet, Ivelin S. Georgiev, Marie Pancera, Tongqing Zhou, Reha-Baris Incesu, Brooks Zhongzheng Fu, Priyanthi N. P. Gnanapragasam, Thiago Y. Oliveira, Michael S. Seaman, Peter D. Kwong, Pamela J. Bjorkman, and Michel C. Nussenzweig. Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization. Cell, 153(1):126-138, 28 Mar 2013. PubMed ID: 23540694. Show all entries for this paper.

Kwong2009a Peter D. Kwong and Ian A. Wilson. HIV-1 and Influenza Antibodies: Seeing Antigens in New Ways. Nat. Immunol., 10(6):573-578, Jun 2009. PubMed ID: 19448659. Show all entries for this paper.

Kwong2011 Peter D. Kwong, John R. Mascola, and Gary J. Nabel. Rational Design of Vaccines to Elicit Broadly Neutralizing Antibodies to HIV-1. Cold Spring Harb. Perspect. Med., 1(1):a007278, Sep 2011. PubMed ID: 22229123. Show all entries for this paper.

Leaman2010 Daniel P. Leaman, Heather Kinkead, and Michael B. Zwick. In-Solution Virus Capture Assay Helps Deconstruct Heterogeneous Antibody Recognition of Human Immunodeficiency Virus Type 1. J. Virol., 84(7):3382-3395, Apr 2010. PubMed ID: 20089658. Show all entries for this paper.

Lin2007 George Lin and Peter L. Nara. Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein. Curr. HIV Res., 5(6):514-541, Nov 2007. PubMed ID: 18045109. Show all entries for this paper.

Pantophlet2010 Ralph Pantophlet. Antibody Epitope Exposure and Neutralization of HIV-1. Curr. Pharm. Des., 16(33):3729-3743, 2010. PubMed ID: 21128886. Show all entries for this paper.

Phogat2007 S. Phogat, R. T. Wyatt, and G. B. Karlsson Hedestam. Inhibition of HIV-1 Entry by Antibodies: Potential Viral and Cellular Targets. J. Intern. Med., 262(1):26-43, Jul 2007. PubMed ID: 17598813. Show all entries for this paper.

Sabin2010 Charles Sabin, Davide Corti, Victor Buzon, Mike S. Seaman, David Lutje Hulsik, Andreas Hinz, Fabrizia Vanzetta, Gloria Agatic, Chiara Silacci, Lara Mainetti, Gabriella Scarlatti, Federica Sallusto, Robin Weiss, Antonio Lanzavecchia, and Winfried Weissenhorn. Crystal Structure and Size-Dependent Neutralization Properties of HK20, a Human Monoclonal Antibody Binding to the Highly Conserved Heptad Repeat 1 of gp41. PLoS Pathog., 6(11):e1001195, 2010. PubMed ID: 21124990. Show all entries for this paper.

Vincent2012 Nadine Vincent and Etienne Malvoisin. Ability of Antibodies Specific to the HIV-1 Envelope Glycoprotein to Block the Fusion Inhibitor T20 in a Cell-Cell Fusion Assay. Immunobiology, 217(10):943-950, Oct 2012. PubMed ID: 22387075. Show all entries for this paper.

Yang2018 Zheng Yang, Xi Liu, Zehua Sun, Jingjing Li, Weiguo Tan, Weiye Yu, and Meiyun Zhang. Identification of a HIV gp41-Specific Human Monoclonal Antibody with Potent Antibody-Dependent Cellular Cytotoxicity. Front. Immunol., 9:2613, 2018. PubMed ID: 30519238. Show all entries for this paper.

Zhou2010 Tongqing Zhou, Ivelin Georgiev, Xueling Wu, Zhi-Yong Yang, Kaifan Dai, Andrés Finzi, Young Do Kwon, Johannes F. Scheid, Wei Shi, Ling Xu, Yongping Yang, Jiang Zhu, Michel C. Nussenzweig, Joseph Sodroski, Lawrence Shapiro, Gary J. Nabel, John R. Mascola, and Peter D. Kwong. Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01. Science, 329(5993):811-817, 13 Aug 2010. PubMed ID: 20616231. Show all entries for this paper.

Displaying record number 1863

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MAb ID	8K8
HXB2 Location	Env	Env Epitope Map
Author Location	gp41
Research Contact	Michael B. Zwick, The Acripps Research Institute, La Jolla, CA, USA, zwick@scripps.edu
Epitope
Ab Type	gp41 NHR (N-heptad repeat), gp41 five-helix bundle (one CHR peptide of six helix bundle is missing)
Neutralizing
Species (Isotype)	rabbit
Patient
Immunogen	vaccine
Keywords	antibody binding site, antibody generation, antibody sequence, binding affinity, neutralization, review, structure, variant cross-reactivity

Vaccine Details

Vaccine type	peptide
Vaccine component	mimotopes
Adjuvant	Incomplete Freund's Adjuvant (IFA)

Notes

Showing 5 of 5 notes.

8K8: This review discusses current understanding of Env neutralization by antibodies in relation to epitope exposure and how this insight might benefit vaccine design strategies. This MAb is in the list of current MAbs with notable cross-neutralizing activity. Pantophlet2010 (neutralization, variant cross-reactivity, review)
8K8: Unlike the MPER MAbs tested, 8K8 did not show any Env-independent virus capture in the conventional or in the modified version of the virus capture assay. Leaman2010
8K8: High level of CDR-H2 sequence similarity was found between 8K8 and Fab 8066. Position 55 was occupied by Gly in both MAbs, but position 56 was Arg in 8K8 and Thr in 8066. Gustchina2010 (structure)
8K8: scFv 8K8 was derived from a rabbit Fab phage display library prepared using the bone marrow RNA extracted from N35ccg-N13 immunized rabbits. The library was screened with N35ccg-N13 peptide, which is a soluble homotrimer corresponding to the HIV-1 gp41 N-heptad repeat (NHR) region. 8K8 bound to N35ccg-N13 but not to recombinant r-gp41 (HXB2) nor to 6-Helix, indicating that 8K8 has a strong preference for gp41 NHRtrimers unoccupied by peptide corresponding to the C-heptad repeat (CHR). In contrast, an IgG engineered form of 8K8 showed weak reactivity with r-gp41 and 6-Helix. 8K8 did not recognize soluble forms of Envs used in typical binding assays, which indicates that the 8K8 epitope is occluded in these Envs. Competition experiments showed that Fab DN9, 8K8, and D5 bind to overlapping but distinct epitopes on the NHR coiled-coil mimetics, where the epitopes of DN9 and 8K8 are more closely related to each other than to D5. Immobilized IgG 8K8 did not capture infectious whole HIV-1 virions in presence or absence of sCD4, indicating that 8K8 epitope is restricted on the NHR trimer on the virion surface. 8K8 has a short CDR H3 (7 residues), and its epitope was suggested to be located in a relatively restricted region of NHR near to the hydrophobic pocket. H564 residue in the NHR region was found critical for 8K8 recognition. In neutralization assays, 8K8 showed modest but relatively broad neutralization, including HIV-1 isolates from both subtypes B and C. HIV-1 JR-FL was resistant to neutralization by 8K8. Neutralization potencies of scFv 8K8 and IgG 8K8 were comparable. Neutralization potency of 8K8 was 1 or 2 orders of magnitude less than that of 4E10. Unlike non-neutralizing Abs in this study, whose heavy chain variable regions were encoded by usually expressed VH1a1 and VH1a2 genes, 8K8 was encoded by a rarely expressed VH gene. Nelson2008 (antibody binding site, antibody generation, neutralization, binding affinity, antibody sequence)
8K8: The neutralization activity of 8K8 is additive with that of N36Mut(e,g) peptide, which is a class 3 inhibitor that disrupts trimerization of the N-heptad repeat (N-HR) in the prehairpin intermediate by sequestering the N-HR into N-HR/N36Mut(e,g) heterodimers. The IC50 for 8K8 alone was estimated to 400 nM, while the IC50 for 8K8 and N36Mut(e,g) in combination was 0.9 nM. Gustchina2008 (neutralization)

References

Showing 5 of 5 references.

Gustchina2008 Elena Gustchina, Carole A. Bewley, and G. Marius Clore. Sequestering of the Prehairpin Intermediate of gp41 by Peptide N36Mut(e,g) Potentiates the Human Immunodeficiency Virus Type 1 Neutralizing Activity of Monoclonal Antibodies Directed against the N-Terminal Helical Repeat of gp41. J. Virol., 82(20):10032-10041, Oct 2008. PubMed ID: 18667502. Show all entries for this paper.

Nelson2008 Josh D. Nelson, Heather Kinkead, Florence M. Brunel, Dan Leaman, Richard Jensen, John M. Louis, Toshiaki Maruyama, Carole A. Bewley, Katherine Bowdish, G. Marius Clore, Philip E. Dawson, Shana Frederickson, Rose G. Mage, Douglas D. Richman, Dennis R. Burton, and Michael B. Zwick. Antibody Elicited against the gp41 N-Heptad Repeat (NHR) Coiled-Coil Can Neutralize HIV-1 with Modest Potency but Non-Neutralizing Antibodies Also Bind to NHR Mimetics. Virology, 377(1):170-183, 20 Jul 2008. PubMed ID: 18499210. Show all entries for this paper.

Pantophlet2010 Ralph Pantophlet. Antibody Epitope Exposure and Neutralization of HIV-1. Curr. Pharm. Des., 16(33):3729-3743, 2010. PubMed ID: 21128886. Show all entries for this paper.

Displaying record number 1891

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MAb ID	DN9
HXB2 Location	Env	Env Epitope Map
Author Location	gp41
Research Contact	Michael B. Zwick, The Acripps Research Institute, La Jolla, CA, USA, zwick@scripps.edu
Epitope
Ab Type	gp41 NHR (N-heptad repeat), gp41 five-helix bundle (one CHR peptide of six helix bundle is missing)
Neutralizing
Species (Isotype)	human
Patient	FDA2
Immunogen	HIV-1 infection
Keywords	antibody binding site, antibody generation, antibody sequence, binding affinity, neutralization, review, structure, variant cross-reactivity

Notes

Showing 4 of 4 notes.

Fab DN9: This review discusses current understanding of Env neutralization by antibodies in relation to epitope exposure and how this insight might benefit vaccine design strategies. This MAb is in the list of current MAbs with notable cross-neutralizing activity. Pantophlet2010 (neutralization, variant cross-reactivity, review)
DN9: Unlike the MPER MAbs tested, DN9 did not show any Env-independent virus capture in the conventional or in the modified version of the virus capture assay. Leaman2010
DN9: High level of CDR-H2 sequence similarity was found between DN9 and Fab 8066. Position 56 was occupied by Thr in both MAbs but position 55 was Glu in DN9 and Gly in 8066. Gustchina2010 (structure)
DN9: Fab DN9 was derived from a human Fab phage display library prepared using the bone marrow RNA extracted from an HIV-1 positive individual (FDA2). The library was screened with N35ccg-N13 peptide, which is a soluble homotrimer corresponding to the HIV-1 gp41 NHR region. DN9 bound to N35ccg-N13 but not to recombinant r-gp41 (HXB2) nor to 6-Helix, indicating that DN9 has a strong preference for NHR trimers unoccupied by peptide corresponding to the C-heptad repeat (CHR). Confirming this, DN9 did not recognize soluble forms of Envs used in typical binding assays, which also indicates that the DN9 epitope is occluded in these Envs. Competition experiments showed that Fab DN9, MAb 8K8, and D5 bind to overlapping but distinct epitopes on the NHR coiled-coil mimetics, where the epitopes of DN9 and 8K8 are more closely related to each other than to D5. DN9 epitope was found distinct from the non-neutralizing Abs in this study, as DN9 does not bind to gp41, gp140, or gp160 as the non-neutralizing Ab did. DN9 has a long CDR H3 (20 residues), and its epitope was suggested to be located in a relatively restricted region of NHR near to the hydrophobic pocket. In neutralization assays, DN9 showed modest but relatively broad neutralization, including HIV-1 isolates from both subtypes B and C. Nelson2008 (antibody binding site, antibody generation, neutralization, binding affinity, antibody sequence)

References

Showing 4 of 4 references.

Isolation Paper
Nelson2008 Josh D. Nelson, Heather Kinkead, Florence M. Brunel, Dan Leaman, Richard Jensen, John M. Louis, Toshiaki Maruyama, Carole A. Bewley, Katherine Bowdish, G. Marius Clore, Philip E. Dawson, Shana Frederickson, Rose G. Mage, Douglas D. Richman, Dennis R. Burton, and Michael B. Zwick. Antibody Elicited against the gp41 N-Heptad Repeat (NHR) Coiled-Coil Can Neutralize HIV-1 with Modest Potency but Non-Neutralizing Antibodies Also Bind to NHR Mimetics. Virology, 377(1):170-183, 20 Jul 2008. PubMed ID: 18499210. Show all entries for this paper.

Pantophlet2010 Ralph Pantophlet. Antibody Epitope Exposure and Neutralization of HIV-1. Curr. Pharm. Des., 16(33):3729-3743, 2010. PubMed ID: 21128886. Show all entries for this paper.

Displaying record number 2055

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MAb ID	Fab 8062
HXB2 Location	Env	Env Epitope Map
Author Location	gp41
Epitope
Ab Type
Neutralizing
Species (Isotype)
Patient
Immunogen	in vitro stimulation or selection
Keywords	antibody binding site, binding affinity, mimotopes, neutralization, structure

Notes

Showing 3 of 3 notes.

8062: Mini-Abs, monovalent and bivalent Fabs targeting the conserved internal trimeric coiled-coil of the Nheptad repeat (N-HR) of gp41 has been previously reported. Crystal structures and binding of closely related monovalent Fabs, Fab 8066 and Fab 8062 to covalently stabilized chimeric trimers of N-peptides of gp41,CCIZN36)3 has been reported. Crystal structures of the complexes between 3-H and Fab 8066 and Fab 8062 were determined at 2.8 and 3.0 A° resolution, respectively. The structural data indicate that binding of three Fabs 8062 with high affinity requires more significant changes in the structure of the N-HR trimer compared to binding of Fab 8066. Gustchina2013 (mimotopes, structure)
8062: Crystal structure of the non-neutralizing 8062 Fab in complex with 5-Helix was compared to the crystal structure of the broadly neutralizing 8066 MAb and MAb D5. For all three Abs, binding affinity correlated with neutralization activity. Structural modeling analyses revealed relatively small differences in the interactions of this Ab with the antigen compared with 8066 and D5. CDR-H2 of 8062 was barely touching the surface of the 5-Helix while CDR-H2 of 8066 was buried in the body of the bundle. Additional interactions, and higher affinity of shared interactions of 8066 compared to 8062 were found, indicating that the difference of 8062 and 8066 in their ability to bind 5-Helix reflects the difference in the neutralization activities of these two MAbs. Gustchina2010 (antibody binding site, binding affinity, structure)
8062: 8062 was derived by affinity maturation of the parent Fab 3674. 8062 bound to the same epitope as the parental Fab and showed improved binding affinity towards the target peptide compared to the parent Fab 3674. However, this Ab did not neutralize any of the laboratory adapted subtype B strains. Gustchina2009 (neutralization, binding affinity)

References

Showing 3 of 3 references.

Gustchina2009 Elena Gustchina, John M. Louis, Christian Frisch, Francisco Ylera, Annette Lechner, Carole A. Bewley, and G. Marius Clore. Affinity Maturation by Targeted Diversification of the CDR-H2 Loop of a Monoclonal Fab Derived from a Synthetic Naive Human Antibody Library and Directed against the Internal Trimeric Coiled-Coil of gp41 Yields a Set of Fabs with Improved HIV-1 Neutralization Potency and Breadth. Virology, 393(1):112-119, 10 Oct 2009. PubMed ID: 19695655. Show all entries for this paper.

Gustchina2013 Elena Gustchina, Mi Li, Rodolfo Ghirlando, Peter Schuck, John M. Louis, Jason Pierson, Prashant Rao, Sriram Subramaniam, Alla Gustchina, G. Marius Clore, and Alexander Wlodawer. Complexes of Neutralizing and Non-Neutralizing Affinity Matured Fabs with a Mimetic of the Internal Trimeric Coiled-Coil of HIV-1 gp41. PLoS One, 8(11):e78187, 2013. PubMed ID: 24244293. Show all entries for this paper.

Displaying record number 2062

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MAb ID	Fab 8066 (8066)
HXB2 Location	Env	Env Epitope Map
Author Location	gp41
Epitope
Ab Type
Neutralizing
Species (Isotype)
Patient
Immunogen	in vitro stimulation or selection
Keywords	ADCC, antibody binding site, binding affinity, mimotopes, neutralization, structure

Notes

Showing 4 of 4 notes.

8066: Isolation of human mAb, E10, from an HIV-1-infected patient sample by single B cell sorting and single cell PCR has been reported. E10 showed binding to gp140 trimer and linear peptides derived from gp41 membrane proximal external region (MPER). IgG E10 use a famous V gene segment IGHV1-69 allelic variants including Fab 8066. Fine mapping of E10 epitope may potentiate MPER-based subunit vaccine development. Yang2018 (ADCC)
8066: Mini-Abs, monovalent and bivalent Fabs targeting the conserved internal trimeric coiled-coil of the Nheptad repeat (N-HR) of gp41 has been previously reported. Crystal structures and binding of closely related monovalent Fabs, Fab 8066 and Fab 8062 to covalently stabilized chimeric trimers of N-peptides of gp41,CCIZN36)3 has been reported. Crystal structures of the complexes between 3-H and Fab 8066 and Fab 8062 were determined at 2.8 and 3.0 A° resolution, respectively. The structural data indicate that binding of three Fabs 8062 with high affinity requires more significant changes in the structure of the N-HR trimer compared to binding of Fab 8066. Gustchina2013 (mimotopes, structure)
8066: Crystal structure of the broadly neutralizing 8066 Fab in complex with 5-Helix was compared to the crystal structure of the non-neutralizing 8062 MAb and MAb D5. For all three Abs, binding affinity correlated with neutralization activity. Structural modeling analyses revealed relatively small differences in the interactions of this Ab with the antigen compared with 8062 and D5. CDR-H2 of 8062 was barely touching the surface of the 5-Helix, while CDR-H2 of 8066 was buried in the body of the bundle. Additional interactions, and higher affinity of shared interactions of 8066 compared to 8062 were found, indicating that the difference of 8062 and 8066 in their ability to bind 5-Helix reflects the difference in the neutralization activities of these two MAbs. Gustchina2010 (antibody binding site, binding affinity, structure)
Fab 8066: 8066 was derived by affinity maturation of the parent Fab 3674. 8066 bound to the same epitope as the parental Fab and showed improved binding affinity towards the target peptide compared to the parent Fab 3674. This was one of three maturated Abs that showed significant increases in both breadth and potency of neutralization against primary isolates of subtypes B and C, compared to the parental Fab. The improved neutralization activity was greater for the Fabs in monovalent than in bivalent formats. Gustchina2009 (neutralization, binding affinity)

References

Showing 4 of 4 references.