Abstract
HIV persistence in reservoirs despite antiretroviral therapy (ART) is a barrier to a permanent cure. We present the affinity-enhanced TCR bispecific IMC-M113V as a potential therapeutic for targeted HIV reservoir elimination. Preclinical studies demonstrate that IMC-M113V redirects T cells towards cells expressing the variable viral peptide, Gag77-85, presented by HLA-A*02:01 at low copy number, without binding to HIV-negative cells. Here, we conduct a first-in-human, open-label single ascending dose study of IMC-M113V (1.6-15 µg) in twelve HLA-A*02:01-positive males living with HIV on suppressive ART (EudraCT number 2021-002008-11). Participants receive one intravenous infusion of IMC-M113V on Day 1 and are monitored through Day 29 to evaluate safety, tolerability (primary endpoints) and pharmacodynamic (PD) activity (secondary endpoint). IMC-M113V is well tolerated and not associated with any serious adverse event. PD activity is dose-dependent and strongest in participants with highly IMC-M113V-sensitive Gag77-85 variant sequences. Thus, we provide a promising foundation to evaluate multiple and higher doses of IMC-M113V as a strategy for achieving ART-free virological control.
Data availability
Key elements of the IMC-M113V-103 study protocol are available at the European Union Clinical Trials Register (EudraCT 2021-002008-11). A redacted version of the IMC-M113V-103 study protocol is included in the Supplementary Information file and available at CTIS - Clinical Trials in the European Union (https://euclinicaltrials.eu). Cell-associated HIV gag RNA sequences generated in this study have been deposited in the BioSample database under BioProject PRJNA1372654 (https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA1372654; https://trace.ncbi.nlm.nih.gov/Traces/study/?acc=SRP650654&o=acc_s%3Aa). Source data are provided with this paper.
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Acknowledgements
The authors thank all participants in the study, as well as the study teams at the participating sites, for their support of this trial and the following employees of Immunocore: M.L. McCully, D. Cuckovic, and C. Perot for assistance with manuscript preparation; D. Berman, J. Suzich and M. Dar for critical review of the manuscript. This study was funded by Immunocore Ltd with support from the Bill and Melinda Gates Foundation. Research reported in this publication was also supported by the National Institute of Allergy and Infectious Diseases under Awards # UM1AI164561 / PO1 AI178376 (MD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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The study was designed by Immunocore (study sponsor) in collaboration with the authors. L.V., J.F., B.M., A.B., Y.Y., J.W., A.D.W, Z.W., P.K.S., L.D., and S.F. contributed to the conception, design and planning of the study. M.D., H.R., J.Cl., J.C., R.H., M.H., S.M., Z.W., and P.K.S. performed assays. L.V., J.F., B.M-P., J.N., S.D.A., A.J.U., S.M.G., M.B., F.A.P., V.E., B.M., and S.F. enroled and treated patients and gathered data. M.D., A.B., H.R., A.T., J.C., R.H., M.H., S.M., Z.W., P.K.S., K.T., and L.D. analysed and interpreted data. A.B., A.D.W., Z.W., P.K.S., K.T., and L.D. drafted the manuscript. All authors critically reviewed iterations of the manuscript and approved the final draft for submission.
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L.V. receives research grants from J&J, ViiV Healthcare and Gilead Sciences. J.N. has received fees for educational activities and/or consultancies and/or financial support for attending conferences from AbbVie, Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme and ViiV Healthcare; S.D.A has received research grants and/or consulting fees from Gilead Sciences, GSK, MSD and ViiV Healthcare. A.J.U. has received financial support for attending a conference from Gilead Sciences. M.B. has received research grants and/or consulting fees from ViiV, Gilead, MSD, GSK, Novavax, Valneva, Cipla, Mylan, Janssen, and Roche. V.E. has received fees for educational activities and/or consultancies and/or financial support for attending conferences from Gilead Sciences, Janssen-Cilag, Merck Sharp and Dohme and ViiV Healthcare. B.M. has received consultancy fees from AELIX Therapeutics SL and AbbVie and speaker fees from Gilead, Janssen and ViiV Healthcare. M.D. was supported by the NIH MDC grant RID-HIV: UM1AI164561 and PO1 AI178376. A.B., H.R., A.T., J.C., R.H., M.H., Y.Y., J.W., S.M., A.D.W., Z.W., P.K.S., K.T., and L.D. were/are employees of Immunocore Ltd. The remaining authors declare no competing interests.
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Vandekerckhove, L., Fox, J., Mora-Peris, B. et al. Safety and biologic activity of a bispecific T cell receptor targeting HIV Gag in males living with HIV: a first-in-human trial. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68833-2
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DOI: https://doi.org/10.1038/s41467-026-68833-2
