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29. Opening the HIV-1 envelope for neutralization and antibody-dependent cellular cytotoxicity

Author

Nguyen, D.N., Richard, J., Tolbert, W.D., Gasser, R., Ding, S., Vezina, D., Gong, S.Y., Lepage, G. Gendron, Medjahed, H., Gottumukkala, S., Prevost, J., Finzi, A., and Pazgier, M.

Subjects
Care and treatment, Research, Methods, Health aspects, Cell therapy -- Methods, HIV infections -- Care and treatment, Fusion proteins -- Health aspects, Fc receptors -- Health aspects, Monoclonal antibodies -- Health aspects, Antibody-dependent cell cytotoxicity -- Research, Immunologic research, Antigenic determinants -- Research, Immunological research, Cellular therapy -- Methods, HIV infection -- Care and treatment
Abstract

OA01.05LB D.N. Nguyen (1); J. Richard (2); W.D. Tolbert (1); R. Gasser (2); S. Ding (2); D. Vezina (2); S.Y. Gong (2); G. Gendron-Lepage (2); H. Medjahed (2); S. Gottumukkala [...], Background: The apparent successes of cancer cure strategies that are based on therapeutic antibodies have caused a re-evaluation of the potential for similar strategies to achieve a functional HIV cure. However, most of the currently explored antibody-based therapies and eradication strategies are based on broadly neutralizing antibodies. By contrast, strategies for a functional cure using non-neutralizing Abs (nnAbs) known to eliminate HIV-infected cells through Fc receptor (FcR) effector functions including antibody-dependent cell mediated cytotoxicity (ADCC) remain a significant yet largely unexploited avenue of research. Highly conserved CD4 inducible (CD4i) epitopes within the constant region 1 and 2 (C1C2 or Cluster A) and the co-receptor binding site (CoRBS) have been shown to be suitable targets for Abs capable of inducing ADCC against infected cells expressing Env in an "open" conformation. As strictly CD4 dependent, these potent ADCC targets become available for Ab recognition upon triggering of Env trimer with cell surface CD4 therefore are occluded and not accessible for Ab targeting on infected cells where expression of CD4 is downregu-lated. Methods: Here we present a structure-based design of new CD4-antibody fusion molecules and evaluate their abilities to sensitize HIV-1-infected cells to ADCC-mediated killing. We developed two classes of Ab fusion proteins in which domains 1 and 2 of soluble human CD4 are linked with either a C1C2 (class 1) or a CoRBS (class 2) specific monoclonal antibody through a flexible ([G.sub.4]S)6([G.sub.4]T)2-linker. We found optimal conjugation sites and linker lengths that allows each of these novel bispecific fusion molecules to recognize the native "closed'' Env trimers and to initiate the structural rearrangements required for exposure of these conserved Env epitopes. Results: Our in vitro functional testing shows that these fusion proteins efficiently target and eliminate HIV infected cells through ADCC activity. Surprisingly, attaching sCD4 to these otherwise non-neutralizing parent cluster A and CoRBS specific Abs has rendered them potent neutralizing activity against tier 1 and 2 viruses. Competition experiments reveal that these biological activities rely on both Ab and CD4 moieties interaction with Env. Conclusions: Altogether, our results raise the exciting possibility of using these fusion proteins in the ongoing efforts to achieve a functional cure.

Published
2021
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