Enhanced HIV-1 neutralization by antibody heteroligation

Area of Science:

• Immunology
• Virology
• Biotechnology

Background:

• Human immunodeficiency virus type 1 (HIV-1) employs evasion strategies against antibody neutralization, including viral spike mutations, glycan shielding, and limited spike expression.
• Limited viral surface spike expression can reduce antibody avidity and neutralizing efficacy.
• Bispecific antibodies (BiAbs) offer a potential strategy to enhance neutralization by engaging multiple viral targets simultaneously.

Purpose of the Study:

• To investigate whether increasing antibody apparent affinity through bispecific binding can enhance HIV-1 neutralization.
• To engineer and evaluate bispecific antibodies targeting both gp120 and gp41 subunits of the HIV-1 envelope glycoprotein (gp160).

Main Methods:

• Engineering of bispecific antibodies (BiAbs) with one scFv arm targeting gp120 and another targeting gp41.
• Assessment of the binding specificities and simultaneous binding capabilities of the engineered BiAbs to gp120 and gp41.
• Evaluation of the neutralizing activity of BiAbs compared to parental antibodies in a macaque model.

Main Results:

• Engineered BiAbs maintained the binding specificities of their parental antibodies.
• Simultaneous binding to gp120 and gp41 by BiAbs was confirmed.
• Heterotypic bivalent binding via BiAbs demonstrated enhanced HIV-1 neutralization compared to parental antibodies.

Conclusions:

• Antibody recognition and HIV-1 neutralization can be improved through heteroligation, a mechanism employed by bispecific antibodies.
• Targeting multiple viral epitopes simultaneously represents a promising strategy to overcome HIV-1 immune evasion.
• Bispecific antibody engineering offers a viable approach to enhance the efficacy of antibody-based HIV-1 therapies.