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• 12A21: This review discusses the identification of super-Abs, where and how such Abs may be best applied and future directions for the field. 12A21 was isolated from human B cell clones and is functionally similar to VRC01. Antigenic region CD4 binding site (Table:1). Walker2018 (antibody binding site, review, broad neutralizer)
• 12A21: HIV-1 escape from the N332-glycan dependent bNAb, PGT135, developed in an elite controller but without change to the PGT135-binding Env epitope itself. Instead an insertion increasing V1 length by up to 21 residues concomitant with an additional 1-3 glycans and 2-4 cysteines shields the epitope from PGT135. The majority of viruses tested developed a 14-fold resistance to PGT135 from month 7 to 11. In comparison, HIV-1 developed a 3 fold resistance against anti-CD4bs bNAb, 12A21, along with mutation at contact residue 462. vandenKerkhof2016 (elite controllers, neutralization, escape)
• 12A21: VRC01-class bNAb like 12A21 protect animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. This paper describes modifications that expand the glVRC01-class antibody-recognition potential of the 426c Env. McGuire2016 (antibody interactions, antibody lineage)
• 12A21: 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. Two versions of germline-binding gp120s were expressed as gp120 cores with N/C termini and V1-V2 and V3 loop truncations, of which 426c.TM4ΔV1-3 binds to germline versions of 12A21. Scharf2016 (structure)
• 12A21: 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. 12A21 was one of the antibodies in the VH-gene-restricted VRC01 class. Zhou2015 (neutralization, structure, antibody lineage, broad neutralizer)
• 12A21_d57: 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. Zhou2013a (antibody sequence, structure, antibody lineage)
• 12A21: 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.)12A21 was used to compare the heavy & light chain sequences as a template of VRC01 class Ab. Zhu2013a (antibody sequence)
• 12A21: 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, neutralization, escape, polyclonal antibodies)
• 12A21: 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, 12A12 family. Kwong2012 (review, structure, broad neutralizer)
• 12A21: 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. 12A21, a CD4bs Ab, was among the 17 bnAbs which were used in studying the mutations in FWR. 12A21 was used in comparing the Ab framework amino acid replacement vs. interactive surface area on Ab. Klein2013 (neutralization, structure, antibody lineage)
• 12A21: 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. 12A21 was studied as anti-CD4BS bnAbs belongs to VRC01 class. When germline reverted light chains of 12A21 was replced by that of NIH45-46/VRC01, the chimeric Abs recognized the 426c NLGS mutant Envs. McGuire2013 (neutralization, antibody lineage)
• 12A21: 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. 12A21 has been referred as an almost PVL in discussing the breadth and potency of antiCD4 abs. West2012a (antibody lineage)
• 12A21: 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. 12A21 bound very strongly to the gp120 core and RSC3, strongly bound to gp120 core D368R, very weakly bound to RSC3/G367R but did not bind to RSC3 Δ3711 and RSC3 Δ3711/P363N. Lynch2012 (binding affinity)
• 12A21: 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. 12A21 arises from IgVH1-2 and IgVK1D-33 germline genes and neutralized 7/8 basic panel isolates, with IC50<24μg/ml and IC80<24μg/ml. 12A21 is polyreactive - reacted with dsDNA, ssDNA, insulin and LPS. Scheid2011 (antibody generation, neutralization, antibody sequence, antibody polyreactivity)

References

Showing 14 of 14 references.

Isolation Paper
Scheid2011 Johannes F. Scheid, Hugo Mouquet, Beatrix Ueberheide, Ron Diskin, Florian Klein, Thiago Y. K. Oliveira, John Pietzsch, David Fenyo, Alexander Abadir, Klara Velinzon, Arlene Hurley, Sunnie Myung, Farid Boulad, Pascal Poignard, Dennis R. Burton, Florencia Pereyra, David D. Ho, Bruce D. Walker, Michael S. Seaman, Pamela J. Bjorkman, Brian T. Chait, and Michel C. Nussenzweig. Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding. Science, 333(6049):1633-1637, 16 Sep 2011. PubMed ID: 21764753. 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.

Kwong2012 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. Show all entries for this paper.

Lynch2012 Rebecca M. Lynch, Lillian Tran, Mark K. Louder, Stephen D. Schmidt, Myron Cohen, CHAVI 001 Clinical Team Members, Rebecca DerSimonian, Zelda Euler, Elin S. Gray, Salim Abdool Karim, Jennifer Kirchherr, David C. Montefiori, Sengeziwe Sibeko, Kelly Soderberg, Georgia Tomaras, Zhi-Yong Yang, Gary J. Nabel, Hanneke Schuitemaker, Lynn Morris, Barton F. Haynes, and John R. Mascola. The Development of CD4 Binding Site Antibodies during HIV-1 Infection. J. Virol., 86(14):7588-7595, Jul 2012. PubMed ID: 22573869. Show all entries for this paper.

McGuire2013 Andrew T. McGuire, Sam Hoot, Anita M. Dreyer, Adriana Lippy, Andrew Stuart, Kristen W. Cohen, Joseph Jardine, Sergey Menis, Johannes F. Scheid, Anthony P. West, William R. Schief, and Leonidas Stamatatos. Engineering HIV Envelope Protein To Activate Germline B Cell Receptors of Broadly Neutralizing Anti-CD4 Binding Site Antibodies. J. Exp. Med., 210(4):655-663, 8 Apr 2013. PubMed ID: 23530120. Show all entries for this paper.

McGuire2016 Andrew T. McGuire, Matthew D. Gray, Pia Dosenovic, Alexander D. Gitlin, Natalia T. Freund, John Petersen, Colin Correnti, William Johnsen, Robert Kegel, Andrew B. Stuart, Jolene Glenn, Michael S. Seaman, William R. Schief, Roland K. Strong, Michel C. Nussenzweig, and Leonidas Stamatatos. Specifically Modified Env Immunogens Activate B-Cell Precursors of Broadly Neutralizing HIV-1 Antibodies in Transgenic Mice. Nat. Commun., 7:10618, 24 Feb 2016. PubMed ID: 26907590. Show all entries for this paper.

Sather2012 D. Noah Sather, Sara Carbonetti, Jenny Kehayia, Zane Kraft, Iliyana Mikell, Johannes F. Scheid, Florian Klein, and Leonidas Stamatatos. Broadly Neutralizing Antibodies Developed by an HIV-Positive Elite Neutralizer Exact a Replication Fitness Cost on the Contemporaneous Virus. J. Virol., 86(23):12676-12685, Dec 2012. PubMed ID: 22973035. Show all entries for this paper.

Scharf2016 Louise Scharf, Anthony P. West, Jr., Stuart A. Sievers, Courtney Chen, Siduo Jiang, Han Gao, Matthew D. Gray, Andrew T. McGuire, Johannes F. Scheid, Michel C. Nussenzweig, Leonidas Stamatatos, and Pamela J. Bjorkman. Structural Basis for Germline Antibody Recognition of HIV-1 Immunogens. Elife, 5, 21 Mar 2016. PubMed ID: 26997349. Show all entries for this paper.

vandenKerkhof2016 Tom L. G. M. van den Kerkhof, Steven W. de Taeye, Brigitte D. Boeser-Nunnink, Dennis R. Burton, Neeltje A. Kootstra, Hanneke Schuitemaker, Rogier W. Sanders, and Marit J. van Gils. HIV-1 escapes from N332-directed antibody neutralization in an elite neutralizer by envelope glycoprotein elongation and introduction of unusual disulfide bonds. Retrovirology, 13(1):48, 7 Jul 2016. PubMed ID: 27388013. Show all entries for this paper.

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. Show all entries for this paper.

West2012a Anthony P. West, Jr., Ron Diskin, Michel C. Nussenzweig, and Pamela J. Bjorkman. Structural Basis for Germ-Line Gene Usage of a Potent Class of Antibodies Targeting the CD4-Binding Site of HIV-1 gp120. Proc. Natl. Acad. Sci. U.S.A., 109(30):E2083-E2090, 24 Jul 2012. PubMed ID: 22745174. Show all entries for this paper.

Zhou2013a Tongqing Zhou, Jiang Zhu, Xueling Wu, Stephanie Moquin, Baoshan Zhang, Priyamvada Acharya, Ivelin S. Georgiev, Han R. Altae-Tran, Gwo-Yu Chuang, M. Gordon Joyce, Young Do Kwon, Nancy S. Longo, Mark K. Louder, Timothy Luongo, Krisha McKee, Chaim A. Schramm, Jeff Skinner, Yongping Yang, Zhongjia Yang, Zhenhai Zhang, Anqi Zheng, Mattia Bonsignori, Barton F. Haynes, Johannes F. Scheid, Michel C. Nussenzweig, Melissa Simek, Dennis R. Burton, Wayne C. Koff, NISC Comparative Sequencing Program, James C. Mullikin, Mark Connors, Lawrence Shapiro, Gary J. Nabel, John R. Mascola, and Peter D. Kwong. Multidonor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for HIV-1 Neutralization by VRC01-Class Antibodies. Immunity, 39(2):245-258, 22 Aug 2013. PubMed ID: 23911655. Show all entries for this paper.

Zhou2015 Tongqing Zhou, Rebecca M. Lynch, Lei Chen, Priyamvada Acharya, Xueling Wu, Nicole A. Doria-Rose, M. Gordon Joyce, Daniel Lingwood, Cinque Soto, Robert T. Bailer, Michael J. Ernandes, Rui Kong, Nancy S. Longo, Mark K. Louder, Krisha McKee, Sijy O'Dell, Stephen D. Schmidt, Lillian Tran, Zhongjia Yang, Aliaksandr Druz, Timothy S. Luongo, Stephanie Moquin, Sanjay Srivatsan, Yongping Yang, Baoshan Zhang, Anqi Zheng, Marie Pancera, Tatsiana Kirys, Ivelin S. Georgiev, Tatyana Gindin, Hung-Pin Peng, An-Suei Yang, NISC Comparative Sequencing Program, James C. Mullikin, Matthew D. Gray, Leonidas Stamatatos, Dennis R. Burton, Wayne C. Koff, Myron S. Cohen, Barton F. Haynes, Joseph P. Casazza, Mark Connors, Davide Corti, Antonio Lanzavecchia, Quentin J. Sattentau, Robin A. Weiss, Anthony P. West, Jr., Pamela J. Bjorkman, Johannes F. Scheid, Michel C. Nussenzweig, Lawrence Shapiro, John R. Mascola, and Peter D. Kwong. Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors. Cell, 161(6):1280-1292, 4 Jun 2015. PubMed ID: 26004070. Show all entries for this paper.

Zhu2013a Jiang Zhu, Xueling Wu, Baoshan Zhang, Krisha McKee, Sijy O'Dell, Cinque Soto, Tongqing Zhou, Joseph P. Casazza, NISC Comparative Sequencing Program, James C. Mullikin, Peter D. Kwong, John R. Mascola, and Lawrence Shapiro. De Novo Identification of VRC01 Class HIV-1-Neutralizing Antibodies by Next-Generation Sequencing of B-Cell Transcripts. Proc. Natl. Acad. Sci. U.S.A., 110(43):E4088-E4097, 22 Oct 2013. PubMed ID: 24106303. Show all entries for this paper.