Antibody 10-1074 suppresses viremia in HIV-1-infected individuals

Marina Caskey; Till Schoofs; Henning Gruell; Allison Settler; Theodora Karagounis; Edward F. Kreider; Ben Murrell; Nico Pfeifer; Lilian Nogueira; Thiago Y. Oliveira; Gerald H. Learn; Yehuda Z. Cohen; Clara Lehmann; Daniel Gillor; Irina Shimeliovich; Cecilia Unson-O'Brien; Daniela Weiland; Alexander Robles; Tim Kümmerle; Christoph Wyen; Rebeka Levin; Maggi Witmer-Pack; Kemal Eren; Caroline Ignacio; Szilard Kiss; Anthony P. West; Hugo Mouquet; Barry S. Zingman; Roy M. Gulick; Tibor Keler; Pamela J. Bjorkman; Michael S. Seaman; Beatrice H. Hahn; Gerd Fätkenheuer; Sarah J. Schlesinger; Michel C. Nussenzweig; Florian Klein

doi:10.1038/nm.4268

Antibody 10-1074 suppresses viremia in HIV-1-infected individuals

Marina Caskey, Till Schoofs, Henning Gruell, Allison Settler, Theodora Karagounis, Edward F. Kreider, Ben Murrell, Nico Pfeifer, Lilian Nogueira, Thiago Y. Oliveira, Gerald H. Learn, Yehuda Z. Cohen, Clara Lehmann, Daniel Gillor, Irina Shimeliovich, Cecilia Unson-O'Brien, Daniela Weiland, Alexander Robles, Tim Kümmerle, Christoph WyenRebeka Levin, Maggi Witmer-Pack, Kemal Eren, Caroline Ignacio, Szilard Kiss, Anthony P. West, Hugo Mouquet, Barry S. Zingman, Roy M. Gulick, Tibor Keler, Pamela J. Bjorkman, Michael S. Seaman, Beatrice H. Hahn, Gerd Fätkenheuer, Sarah J. Schlesinger, Michel C. Nussenzweig, Florian Klein

Medicine

Research output: Contribution to journal › Article › peer-review

178 Scopus citations

Abstract

Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log 10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.

Original language	English (US)
Pages (from-to)	185-191
Number of pages	7
Journal	Nature Medicine
Volume	23
Issue number	2
DOIs	https://doi.org/10.1038/nm.4268
State	Published - Feb 1 2017

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/nm.4268

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Caskey, M., Schoofs, T., Gruell, H., Settler, A., Karagounis, T., Kreider, E. F., Murrell, B., Pfeifer, N., Nogueira, L., Oliveira, T. Y., Learn, G. H., Cohen, Y. Z., Lehmann, C., Gillor, D., Shimeliovich, I., Unson-O'Brien, C., Weiland, D., Robles, A., Kümmerle, T., ... Klein, F. (2017). Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. Nature Medicine, 23(2), 185-191. https://doi.org/10.1038/nm.4268

Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. / Caskey, Marina; Schoofs, Till; Gruell, Henning; Settler, Allison; Karagounis, Theodora; Kreider, Edward F.; Murrell, Ben; Pfeifer, Nico; Nogueira, Lilian; Oliveira, Thiago Y.; Learn, Gerald H.; Cohen, Yehuda Z.; Lehmann, Clara; Gillor, Daniel; Shimeliovich, Irina; Unson-O'Brien, Cecilia; Weiland, Daniela; Robles, Alexander; Kümmerle, Tim; Wyen, Christoph; Levin, Rebeka; Witmer-Pack, Maggi; Eren, Kemal; Ignacio, Caroline; Kiss, Szilard; West, Anthony P.; Mouquet, Hugo; Zingman, Barry S.; Gulick, Roy M.; Keler, Tibor; Bjorkman, Pamela J.; Seaman, Michael S.; Hahn, Beatrice H.; Fätkenheuer, Gerd; Schlesinger, Sarah J.; Nussenzweig, Michel C.; Klein, Florian.

In: Nature Medicine, Vol. 23, No. 2, 01.02.2017, p. 185-191.

Research output: Contribution to journal › Article › peer-review

Caskey, M, Schoofs, T, Gruell, H, Settler, A, Karagounis, T, Kreider, EF, Murrell, B, Pfeifer, N, Nogueira, L, Oliveira, TY, Learn, GH, Cohen, YZ, Lehmann, C, Gillor, D, Shimeliovich, I, Unson-O'Brien, C, Weiland, D, Robles, A, Kümmerle, T, Wyen, C, Levin, R, Witmer-Pack, M, Eren, K, Ignacio, C, Kiss, S, West, AP, Mouquet, H, Zingman, BS, Gulick, RM, Keler, T, Bjorkman, PJ, Seaman, MS, Hahn, BH, Fätkenheuer, G, Schlesinger, SJ, Nussenzweig, MC & Klein, F 2017, 'Antibody 10-1074 suppresses viremia in HIV-1-infected individuals', Nature Medicine, vol. 23, no. 2, pp. 185-191. https://doi.org/10.1038/nm.4268

Caskey, Marina ; Schoofs, Till ; Gruell, Henning ; Settler, Allison ; Karagounis, Theodora ; Kreider, Edward F. ; Murrell, Ben ; Pfeifer, Nico ; Nogueira, Lilian ; Oliveira, Thiago Y. ; Learn, Gerald H. ; Cohen, Yehuda Z. ; Lehmann, Clara ; Gillor, Daniel ; Shimeliovich, Irina ; Unson-O'Brien, Cecilia ; Weiland, Daniela ; Robles, Alexander ; Kümmerle, Tim ; Wyen, Christoph ; Levin, Rebeka ; Witmer-Pack, Maggi ; Eren, Kemal ; Ignacio, Caroline ; Kiss, Szilard ; West, Anthony P. ; Mouquet, Hugo ; Zingman, Barry S. ; Gulick, Roy M. ; Keler, Tibor ; Bjorkman, Pamela J. ; Seaman, Michael S. ; Hahn, Beatrice H. ; Fätkenheuer, Gerd ; Schlesinger, Sarah J. ; Nussenzweig, Michel C. ; Klein, Florian. / Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. In: Nature Medicine. 2017 ; Vol. 23, No. 2. pp. 185-191.

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title = "Antibody 10-1074 suppresses viremia in HIV-1-infected individuals",

abstract = "Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log 10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.",

author = "Marina Caskey and Till Schoofs and Henning Gruell and Allison Settler and Theodora Karagounis and Kreider, {Edward F.} and Ben Murrell and Nico Pfeifer and Lilian Nogueira and Oliveira, {Thiago Y.} and Learn, {Gerald H.} and Cohen, {Yehuda Z.} and Clara Lehmann and Daniel Gillor and Irina Shimeliovich and Cecilia Unson-O'Brien and Daniela Weiland and Alexander Robles and Tim K{\"u}mmerle and Christoph Wyen and Rebeka Levin and Maggi Witmer-Pack and Kemal Eren and Caroline Ignacio and Szilard Kiss and West, {Anthony P.} and Hugo Mouquet and Zingman, {Barry S.} and Gulick, {Roy M.} and Tibor Keler and Bjorkman, {Pamela J.} and Seaman, {Michael S.} and Hahn, {Beatrice H.} and Gerd F{\"a}tkenheuer and Schlesinger, {Sarah J.} and Nussenzweig, {Michel C.} and Florian Klein",

note = "Funding Information: Amplification and library preparation for SMRT sequencing was performed with the support of the Translational Virology Core at the UC San Diego Center for AIDS Research (P30 AI036214). SMRT sequencing was conducted at the IGM Genomics Center, University of California, San Diego, La Jolla, California. Computational analysis of sequence data was performed, in part, on a cluster, which was supported by U01 GM110749 (NIH/NIGMS). This work was supported in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) Grants OPP1032144 (M.S.S.), OPP1092074 and OPP1124068 (M.C.N.), National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grant HIVRAD P01 AI100148 (P.J.B.), a BEAT-HIV Delaney grant UM1 AI126620 (B.H.H.), the Robertson Foundation to M.C.N., and the NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (M.C.N.). T.S. was supported by a German Research Foundation postdoctoral fellowship (SCHO 1612/1-1) and is currently supported in part by grant #UL1 TR001866 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program. H.G. is supported by a fellowship from the German Center for Infection Research (DZIF). T. Karagounis is an HHMI Medical Research Fellow. E.F.K. is supported by a Ruth L. Kirschstein National Research Service Award (F30 AI112426). B.M. was supported by grant number R00 AI120851 from the National Institute of Allergy and Infectious Diseases. K.E. was supported by T15 LM007092 from the National Library of Medicine. F.K. is supported by the Heisenberg Program of the DFG (KL 2389/2-1), the European Research Council (ERC-StG639961) and the German Center for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany.",

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T1 - Antibody 10-1074 suppresses viremia in HIV-1-infected individuals

AU - Caskey, Marina

AU - Schoofs, Till

AU - Gruell, Henning

AU - Settler, Allison

AU - Karagounis, Theodora

AU - Kreider, Edward F.

AU - Murrell, Ben

AU - Pfeifer, Nico

AU - Nogueira, Lilian

AU - Oliveira, Thiago Y.

AU - Learn, Gerald H.

AU - Cohen, Yehuda Z.

AU - Lehmann, Clara

AU - Gillor, Daniel

AU - Shimeliovich, Irina

AU - Unson-O'Brien, Cecilia

AU - Weiland, Daniela

AU - Robles, Alexander

AU - Kümmerle, Tim

AU - Wyen, Christoph

AU - Levin, Rebeka

AU - Witmer-Pack, Maggi

AU - Eren, Kemal

AU - Ignacio, Caroline

AU - Kiss, Szilard

AU - West, Anthony P.

AU - Mouquet, Hugo

AU - Zingman, Barry S.

AU - Gulick, Roy M.

AU - Keler, Tibor

AU - Bjorkman, Pamela J.

AU - Seaman, Michael S.

AU - Hahn, Beatrice H.

AU - Fätkenheuer, Gerd

AU - Schlesinger, Sarah J.

AU - Nussenzweig, Michel C.

AU - Klein, Florian

N1 - Funding Information: Amplification and library preparation for SMRT sequencing was performed with the support of the Translational Virology Core at the UC San Diego Center for AIDS Research (P30 AI036214). SMRT sequencing was conducted at the IGM Genomics Center, University of California, San Diego, La Jolla, California. Computational analysis of sequence data was performed, in part, on a cluster, which was supported by U01 GM110749 (NIH/NIGMS). This work was supported in part by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) Grants OPP1032144 (M.S.S.), OPP1092074 and OPP1124068 (M.C.N.), National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grant HIVRAD P01 AI100148 (P.J.B.), a BEAT-HIV Delaney grant UM1 AI126620 (B.H.H.), the Robertson Foundation to M.C.N., and the NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (M.C.N.). T.S. was supported by a German Research Foundation postdoctoral fellowship (SCHO 1612/1-1) and is currently supported in part by grant #UL1 TR001866 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program. H.G. is supported by a fellowship from the German Center for Infection Research (DZIF). T. Karagounis is an HHMI Medical Research Fellow. E.F.K. is supported by a Ruth L. Kirschstein National Research Service Award (F30 AI112426). B.M. was supported by grant number R00 AI120851 from the National Institute of Allergy and Infectious Diseases. K.E. was supported by T15 LM007092 from the National Library of Medicine. F.K. is supported by the Heisenberg Program of the DFG (KL 2389/2-1), the European Research Council (ERC-StG639961) and the German Center for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany.

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N2 - Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log 10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.

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