Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute hepatitis C virus infection in mice

Zhen Yong Keck, Yong Wang, Patrick Lau, Garry Lund, Sneha Rangarajan, Catherine Fauvelle, Grant C. Liao, Frederick W. Holtsberg, Kelly L. Warfield, M. Javad Aman, Brian G. Pierce, Thomas R. Fuerst, Justin R. Bailey, Thomas F. Baumert, Roy A. Mariuzza, Norman M. Kneteman, Steven K H Foung

Research output: Research - peer-reviewArticle

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 use 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 an HMAb that is less likely to elicit RAVs for affinity maturation to increase potency and, more important, 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. Conclusion: 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. (Hepatology 2016;64:1922-1933).

LanguageEnglish (US)
Pages1922-1933
Number of pages12
JournalHepatology
Volume64
Issue number6
DOIs
StatePublished - Dec 1 2016

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Virus Diseases
Hepacivirus
Monoclonal Antibodies
Antiviral Agents
Antibodies
Infection
Serum
Hepatovirus
Antibodies, Monoclonal, Humanized
Chronic Hepatitis C
Gastroenterology
Neutralizing Antibodies
Treatment Failure
Sequence Analysis
Epitopes
Viruses
Light
Mutation
Clinical Studies

ASJC Scopus subject areas

  • Hepatology

Cite this

Keck, Z. Y., Wang, Y., Lau, P., Lund, G., Rangarajan, S., Fauvelle, C., ... Foung, S. K. H. (2016). Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute hepatitis C virus infection in mice. Hepatology, 64(6), 1922-1933. DOI: 10.1002/hep.28850

Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute hepatitis C virus infection in mice. / Keck, Zhen Yong; Wang, Yong; Lau, Patrick; Lund, Garry; Rangarajan, Sneha; Fauvelle, Catherine; Liao, Grant C.; Holtsberg, Frederick W.; Warfield, Kelly L.; Aman, M. Javad; Pierce, Brian G.; Fuerst, Thomas R.; Bailey, Justin R.; Baumert, Thomas F.; Mariuzza, Roy A.; Kneteman, Norman M.; Foung, Steven K H.

In: Hepatology, Vol. 64, No. 6, 01.12.2016, p. 1922-1933.

Research output: Research - peer-reviewArticle

Keck, ZY, Wang, Y, Lau, P, Lund, G, Rangarajan, S, Fauvelle, C, Liao, GC, Holtsberg, FW, Warfield, KL, Aman, MJ, Pierce, BG, Fuerst, TR, Bailey, JR, Baumert, TF, Mariuzza, RA, Kneteman, NM & Foung, SKH 2016, 'Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute hepatitis C virus infection in mice' Hepatology, vol 64, no. 6, pp. 1922-1933. DOI: 10.1002/hep.28850
Keck ZY, Wang Y, Lau P, Lund G, Rangarajan S, Fauvelle C et al. Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute hepatitis C virus infection in mice. Hepatology. 2016 Dec 1;64(6):1922-1933. Available from, DOI: 10.1002/hep.28850
Keck, Zhen Yong ; Wang, Yong ; Lau, Patrick ; Lund, Garry ; Rangarajan, Sneha ; Fauvelle, Catherine ; Liao, Grant C. ; Holtsberg, Frederick W. ; Warfield, Kelly L. ; Aman, M. Javad ; Pierce, Brian G. ; Fuerst, Thomas R. ; Bailey, Justin R. ; Baumert, Thomas F. ; Mariuzza, Roy A. ; Kneteman, Norman M. ; Foung, Steven K H. / Affinity maturation of a broadly neutralizing human monoclonal antibody that prevents acute hepatitis C virus infection in mice. In: Hepatology. 2016 ; Vol. 64, No. 6. pp. 1922-1933
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