Anti-CD4 monoclonal antibody ibalizumab exhibits breadth and potency against HIV-1, with natural resistance mediated by the loss of a V5 glycan in envelope.

Abstract

OBJECTIVES:

Passive immunization for the prevention of HIV-1 infection is currently being reenergized. The anti-CD4 monoclonal antibody ibalizumab has demonstrated safety and efficacy in phase 1 and 2 clinical trials for treatment of HIV-1 infection and is undergoing a phase 1 clinical trial in HIV-1 uninfected individuals for prevention. Here, we sought to assess ibalizumab antiviral breadth and potency and to identify determinants of natural preexisting resistance.

METHODS:

Ibalizumab breadth and potency was assessed against a large clinically relevant panel of HIV-1 pseudoviruses (n = 116) commonly used to assess vaccine candidates. Determinants of resistance were assessed by sequence analysis.

RESULTS:

Ibalizumab neutralized 92% and 66% of viruses as defined by 50% and 80% inhibition, respectively. Median in vitro neutralization potency by IC50 was 0.03 μg/mL, substantially lower than the broadly neutralizing mAbs, PG9, or VRC01. The dominant determinant of resistance was the absence of a potential N-linked glycosylation site (PNGS) at the V5 N-terminus (P < 0.001), with the V2 loop length possibly influencing the degree of resistance afforded by the absence of the V5 N-terminal PNGS (P = 0.001). Other significant independent correlates of resistance included PNGS at position 386 and the side chain length of residue 375. Ibalizumab exhibited complementary resistance to VRC01 (P = 0.006) and sCD4 (P < 0.001), in part mediated by the V5 PNGS.

CONCLUSIONS:

Ibalizumab breadth and potency compared favorably with broadly neutralizing anti-HIV-1 monoclonal antibodies, supporting the clinical development of ibalizumab, alone or in combination, for HIV-1 prevention.

• Authors: Craig S Pace, Marshall W Fordyce, David Franco, Chia-Ying Kao, Michael S Seaman, David D Ho
• Journal: Journal of acquired immune deficiency syndromes (1999) (J Acquir Immune Defic Syndr) Vol. 62 Issue 1 Pg. 1-9 (Jan 01 2013) ISSN: 1944-7884 [Electronic] United States
• PMID: 23023102 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Antibodies, Monoclonal
• Antibodies, Neutralizing
• ibalizumab

Topics

• Anti-HIV Agents (pharmacology)
• Antibodies, Monoclonal (immunology, pharmacology)
• Antibodies, Neutralizing (immunology)
• Drug Resistance, Viral
• HIV Infections (virology)
• HIV-1 (drug effects)
• Humans
• Inhibitory Concentration 50
• Neutralization Tests