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Bifunctional fusion proteins of the human engineered antibody domain m36 with human soluble CD4 are potent inhibitors of diverse HIV-1 isolates.

Abstract：

:Currently used antiretroviral therapy is highly successful but there is still a need for new effective and safe prophylactics and therapeutics. We have previously identified and characterized a human engineered antibody domain (eAd), m36, which exhibits potent broadly neutralizing activity against HIV-1 by targeting a highly conserved CD4 binding-induced (CD4i) structure on the viral envelope glycoprotein (Env) gp120. m36 has very small size (∼15kDa) but is highly specific and is likely to be safe in long-term use thus representing a novel class of potentially promising HIV-1 inhibitors. Major problems with the development of m36 as a candidate therapeutic are possible short serum half life and lack of effector functions that could be important for effective protection in vivo. Fusion of m36 to human IgG1 Fc resulted in dramatically diminished neutralization potency most likely due to the sterically restricted nature of the m36 epitope that limits access of large molecules. To confer effector functions and simultaneously increase the potency, we first matured m36 by panning and screening a mutant library for mutants with increased binding to gp120. We next fused m36 and its mutants with the first two domains (soluble CD4, sCD4) of the human CD4 using a polypeptide linker. Our results showed that the selected m36 mutants and the sCD4 fusion proteins exhibited more potent antiviral activities than m36. The m36-sCD4 fusion proteins with human IgG1 Fc showed even higher potency likely due to their bivalency and increased avidity although with a greater increase in molecular size. Our data suggest that m36 derivatives are promising HIV-1 candidate therapeutics and tools to study highly conserved gp120 structures with implications for understanding mechanisms of entry and design of vaccine immunogens and small-molecule inhibitors.

journal_name

Antiviral Res

journal_title

Antiviral research

authors

Chen W,Xiao X,Wang Y,Zhu Z,Dimitrov DS

doi

10.1016/j.antiviral.2010.08.004

subject

Has Abstract

pub_date

2010-10-01 00:00:00

pages

107-15

issue

eissn

0166-3542

issn

1872-9096

pii

S0166-3542(10)00691-1

journal_volume

pub_type

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Bifunctional fusion proteins of the human engineered antibody domain m36 with human soluble CD4 are potent inhibitors of diverse HIV-1 isolates.