Engineering pan–HIV-1 neutralization potency through multispecific antibody avidity
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Date
2022-01-25Author
Rujas Díez, Edurne
Cui, Hong
Burnie, Jonathan
Burn Aschner, Clare
Zhao, Tiantian
Insausti González, Sara
Muthuraman, Krithika
Semesi, Anthony
Ophel, Jasper
Nieva Escandón, José Luis
Seaman, Michael S.
Guzzo, Christina
Treanor, Bebhinn
Julien, Jean-Philippe
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Proceedings of the National Academy of Sciences of the United States of America 119(4) : (2022) // Article ID e2112887119
Abstract
Deep mining of B cell repertoires of HIV-1-infected individuals has resulted in the isolation of dozens of HIV-1 broadly neutralizing antibodies (bNAbs). Yet, it remains uncertain whether any such bNAbs alone are sufficiently broad and potent to deploy therapeutically. Here, we engineered HIV-1 bNAbs for their combination on a single multispecific and avid molecule via direct genetic fusion of their Fab fragments to the human apoferritin light chain. The resulting molecule demonstrated a remarkable median IC50 value of 0.0009 g/mL and 100% neutralization coverage of a broad HIV-1 pseudovirus panel (118 isolates) at a 4 g/mL cutoff-a 32-fold enhancement in viral neutralization potency compared to a mixture of the corresponding HIV-1 bNAbs. Importantly, Fc incorporation on the molecule and engineering to modulate Fc receptor binding resulted in IgG-like bioavailability invivo. This robust plug-and-play antibody design is relevant against indications where multispecificity and avidity are leveraged simultaneously to mediate optimal biological activity.