Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute HCV infection.

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TitleAffinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute HCV infection.
Publication TypeJournal Article
Year of Publication2016
AuthorsKeck, Z-Y, Wang, Y, Lau, P, Lund, G, Rangarajan, S, Fauvelle, C, Liao, GC, Holtsberg, FW, Warfield, KL, M Aman, J, Pierce, BG, Fuerst, TR, Bailey, JR, Baumert, TF, Mariuzza, RA, Kneteman, NM, Foung, SKH
JournalHepatology
Date Published2016 Sep 19
ISSN1527-3350
Abstract

Direct acting antivirals (DAAs) have led to a high cure rate in treated patients with chronic hepatitis C virus (HCV) infection but this still leaves a large number of treatment failures secondary to the emergence of resistance-associated variants (RAVs). To increase the barrier to resistance, a complementary strategy is to employ neutralizing human monoclonal antibodies (HMAbs) to prevent acute infection. However, earlier efforts with the selected antibodies led to RAVs in animal and clinical studies. Therefore, we identified a HMAb that is less likely to elicit RAVs for affinity maturation to increase potency and, more importantly, breadth of protection. Selected matured antibodies show improved affinity and neutralization against a panel of diverse HCV isolates. Structural and modeling studies reveal that the affinity matured HMAb mediates virus neutralization in part by inducing conformational change to the targeted epitope and that the maturated light chain is responsible for the improved affinity and breadth of protection. A matured HMAb protected humanized mice when challenged with an infectious HCV human serum inoculum for a prolonged period. However, a single mouse experienced breakthrough infection after 63 days when the serum HMAb concentration dropped by several logs; sequence analysis revealed no viral escape mutation.

CONCLUSIONS: The findings suggest that a single broadly neutralizing antibody can prevent acute HCV infection without inducing RAVs and may complement DAAs to reduce the emergence of RAVs. This article is protected by copyright. All rights reserved.

DOI10.1002/hep.28850
Alternate JournalHepatology
PubMed ID27641232