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Combination therapy with anti-HIV-1 antibodies maintains viral suppression

Mendoza, Pilar and West, Anthony P., Jr. and Bjorkman, Pamela J. (2018) Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature, 561 (7724). pp. 479-484. ISSN 0028-0836. PMCID PMC6166473. https://resolver.caltech.edu/CaltechAUTHORS:20180723-120809364

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[img] Image (JPEG) (Extended Data Fig. 1: Study participant selection and demographics) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 2: Demographics, CD4^+ T cells during study period in participants and pharmacokinetics of 3BNC117 and 10-1074) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 3: Phylogenetic tree of viruses from all enrolled participants) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 4: Viral rebound, amino acid variants at 10-1074 contact sites and sensitivities of latent and rebound viruses in the participants with detectable viraemia (>20 copies per ml) two weeks before or at the start of ATI) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 5: Phylogenetic env trees and TZM-bl neutralization curves for individuals with viral blips) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 6: Amino acid variants at 3BNC117 contact sites of reactivated latent and rebound viruses) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 7: Comparison of the circulating latent reservoir and rebound viruses) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 8: Recombination events in rebound viruses) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 9: Phylogenetic trees of participants 9245, 9251, 9254 and 9255) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 10: Clonal distribution of the circulating latent reservoir and IUPM changes) - Supplemental Material
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Abstract

Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg^(−1) of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41586-018-0531-2DOIArticle
https://rdcu.be/7RzePublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166473PubMed CentralArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2018 Springer Nature Limited. Received: 6 June 2018; Accepted: 30 July 2018; Published online 26 September 2018. We thank all study participants who devoted time to our research; members of the Klein and Nussenzweig laboratories for helpful discussions, especially Y. Bar-On, L. Cohn and M. Jankovic; R. Levin for study coordination and the Rockefeller University Hospital Clinical Research Support Office and nursing staff as well as K. Fiddike, C. Golder, S. Margane, M. Platten, E. Voigt and D. Weiland for help with recruitment and study implementation; K. Jain for help with sample processing; S. Kiss for ophthalmologic assessments; T. Keler and the Celldex Therapeutics team for 3BNC117 and 10-1074 manufacturing and regulatory support; C. Conrad for regulatory support; U. Kerkweg, R. Macarthur and A. Johnson for pharmaceutical services; H. Janicki, M. Ercanoglu, P. Schommers and R. Kaiser for help with virus cultures; C. Scheid and U. Holtick for leukaphereses; S. McMillan, S. Mosher, S. Sawant, D. Beaumont, M. Sarzotti-Kelsoe, K. Greene, H. Gao and D. Montefiori for help with PK assay development, validation, reporting, and/or project management; P. Fast and H. Park for clinical monitoring; and S. Schlesinger for input on study design. This work was supported by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grants OPP1092074, OPP1124068 (M.C.N.), CAVIMC OPP1146996 (G.D.T., M.S.S.); the Heisenberg-Program of the DFG (KL 2389/2-1), the European Research Council (ERC-StG639961), and the German Center for Infection Research (DZIF) (F.K.); the NIH grants 1UM1 AI100663 and R01AI-129795 (M.C.N.); the Einstein-Rockefeller-CUNY Center for AIDS Research (1P30AI124414-01A1); BEAT-HIV Delaney grant UM1 AI126620 (M.C.); and the Robertson fund of the Rockefeller University. M.C.N. is a Howard Hughes Medical Institute Investigator. Reviewer information: Nature thanks G. Silvestri and the other anonymous reviewer(s) for their contribution to the peer review of this work. These authors contributed equally: Pilar Mendoza, Henning Gruell. These authors jointly supervised this work: Florian Klein, Marina Caskey, Michel C. Nussenzweig. Author Contributions: M.C. is the principal investigator for the work in the United States and F.K. is the principal investigator for Germany; M.C., F.K. and M.C.N. designed the trial; P.M., H.G., F.K., M.C. and M.C.N. analysed the data and wrote the manuscript; P.M., L.N. and T.Ka. performed Q2VOA, rebound cultures and SGA; H.G., M.W.-P., G.K., E.T., J.H., M.C. and F.K. implemented the study; A.L.B., K.M., Y.Z.C., C.L., I.Su., C.W., T.Kü. and C.S. contributed to recruitment and clinical assessments; P.M., H.G. and L.N. performed bulk viral cultures; J.A.P. and T.Y.O. performed bioinformatics processing; K.E.S. and G.D.T. conducted anti-idiotype ELISA; M.S.S. conducted TZM-bl assays; C.U.-O., R.P., C.R., M.S. and I.Sh. coordinated and performed sample processing; L.H., A.P.W., P.J.B. and N.P. contributed to data analysis; J.C.C.L., C-L.L., R.M.G. and G.F. contributed to study design and implementation. Competing interests: There are patents on 3BNC117 (PTC/US2012/038400) and 10-1074 (PTC/US2013/065696) that list M.C.N. as an inventor. The sequences from all isolated viruses are available in GenBank, accession numbers MH575375–MH576416. Further information on research design is available in the Nature Research Reporting Summary linked to this paper.
Funders:
Funding AgencyGrant Number
Bill and Melinda Gates FoundationOPP1092074
Bill and Melinda Gates FoundationOPP1124068
Bill and Melinda Gates FoundationOPP1146996
Deutsche Forschungsgemeinschaft (DFG)KL 2389/2-1
European Research Council (ERC)639961
Deutsches Zentrum für Infektionsforschung (DZIF)UNSPECIFIED
NIH1UM1 AI100663
NIHR01AI-129795
NIH1P30AI124414-01A1
NIHUM1 AI126620
Rockefeller UniversityUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:7724
PubMed Central ID:PMC6166473
Record Number:CaltechAUTHORS:20180723-120809364
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180723-120809364
Official Citation:Mendoza, P., Gruell, H., Nogueira, L. et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 561, 479–484 (2018) doi:10.1038/s41586-018-0531-2
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:88135
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:27 Sep 2018 16:43
Last Modified:06 Dec 2019 18:03

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