Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo

by R. Rudicell, Y. Kwon, S.Y. Ko, A. Pegu, M. Louder, I. Georgiev, X. Wu, J. Zhu, J. Boyington, X. Chen, W. Shi, Z. Yang, N. Doria-Rose, K. McKee, S. O'Dell, S. Schmidt, G.Y. Chuang, A. Druz, C. Soto, Y. Yang, B. Zhang, T. Zhou, J.P. Todd, K. Lloyd, J. Eudailey, K. Roberts, B. R. Donald, R. Bailer, J. Ledgerwood, NISC Comparative Sequencing Program, J. Mullikin, L. Shapiro, R. Koup, B. Graham, M. Nason, M. Connors, B. Haynes, S. Rao, M. Roederer, P. Kwong, J. Mascola, and G. Nabel.

Vaccine Research Center, NIAID, NIH
Duke University

Journal of Virology 2014; 88(21):12669-82.

Read the paper at JVI website
Pubmed; Abstract; PDF; Supplementary Material; Structures (PDB); Clinical Trials

Summary: In the absence of an effective HIV-1 vaccine, alternative strategies are needed to block HIV-1 transmission. Direct administration of HIV-1-neutralizing antibodies may be able to prevent HIV-1 infections in humans. This approach could be especially useful in individuals at high risk for contracting HIV-1 and could be used together with antiretroviral drugs to prevent infection. To optimize the chance of success, such antibodies can be modified to improve their potency, breadth, and in vivo half-life. Here, knowledge of the structure of a potent neutralizing antibody VRC01, that targets the CD4-binding site of the HIV-1 envelope protein, was used to engineer a next-generation antibody with 5-8 fold increased potency in vitro. When administered to non-human primates, this antibody conferred protection at a five-fold lower concentration than the original antibody.

An important aspect of this work is the ability to optimize an antibody for highest in vivo efficacy using the computational structure-based protein design algorithms embodied in our Osprey software suite. VRC01 targets the conserved CD4 binding site of HIV envelope glycoprotein gp120 and can neutralize ~90% of HIV-1 strains. This mAb has completed phase 1 clinical trials at the NIH, and is now in phase 2. Our novel, iterative, structure-based strategy for improving VRC01 neutralization potency and breadth also provides a model for other anti-viral mAbs. This process resulted in a variant of VRC01, called VRC07-523-LS, that is ~8-fold more potent and could neutralize 96% of viral strains. The optimized mAb has an extended in vivo half-life and demonstrates superior in vivo protective efficacy.

Importantly, the improvements in efficacy and half-life described here will allow for lower antibody doses and extended time between doses, which will make passive immunization more feasible and broadly applicable for AIDS prevention. The designed mAb VRC07-523-LS has now entered clinical trials (see below).

Latest News: A designed antibody from our paper is going into clinical trials:

Pubmed; Abstract; PDF; Supplementary Material; Structures (PDB); Clinical Trials

Read the PDF of the paper at JVI website