Fiche publication
Date publication
décembre 2016
Journal
Hepatology (Baltimore, Md.)
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAUMERT Thomas
Tous les auteurs :
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 SK
Lien Pubmed
Résumé
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.
Mots clés
Animals, Antibodies, Monoclonal, therapeutic use, Antibodies, Neutralizing, therapeutic use, Antibody Affinity, Cells, Cultured, Hepacivirus, immunology, Hepatitis C, prevention & control, Humans, Mice
Référence
Hepatology. 2016 12;64(6):1922-1933
