Journal Article

Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention

Reeves, Daniel B., Mayer, Bryan T., Huang, Yunda, Gottardo, Raphael, Schiffer, Joshua T., deCamp, Allan C., Gilbert, Peter B.

2022

Overview

Broadly neutralizing antibodies (bNAbs) are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As with ART, bNAb combinations are likely needed to cover HIV’s extensive diversity. Not all bNAbs are identical in terms of their breadth, potency, and in vivo longevity (half-life). Given these differences, it is important to optimally select the composition, or dose ratio, of combination bNAb therapies for future clinical studies. We developed a model that synthesizes 1) pharmacokinetics, 2) potency against a wide HIV diversity, 3) interaction models for how drugs work together, and 4) correlates that translate in vitro potency to clinical protection. We found optimization requires drug-specific balances between potency, longevity, and interaction type. As an example, tradeoffs between longevity and potency are shown by comparing a combination therapy to a bi-specific antibody (a single protein merging both bNAbs) that takes the better potency but the worse longevity of the two components. Then, we illustrate a realistic dose ratio optimization of a triple combination of VRC07, 3BNC117, and 10–1074 bNAbs. We apply protection estimates derived from both a non-human primate (NHP) challenge study meta-analysis and the human antibody mediated prevention (AMP) trials. In both cases, we find a 2:1:1 dose emphasizing VRC07 is nearly optimal. Our approach can be immediately applied to optimize the next generation of combination antibody prevention and cure studies.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animal models / Animals / Antibodies / Antibodies, Neutralizing / Antiretroviral agents / Antiretroviral drugs / Antiretroviral therapy / Biology and Life Sciences / Broadly Neutralizing Antibodies / Case studies / Clinical trials / Combined Modality Therapy / Disease prevention / Dosage / Drug dosages / Drug interaction / Health aspects / HIV / HIV Antibodies / HIV infection / HIV Infections - drug therapy / HIV Infections - prevention & control / HIV-1 / Human immunodeficiency virus / Infections / Interaction models / Longevity / Mathematical optimization / Medicine and Health Sciences / Microbalances / Neutralizing / Optimization / Pharmacodynamics / Pharmacokinetics / Physical Sciences / Prevention / Remission / Research and Analysis Methods / Viral antibodies / Viral infections / Viruses