Engineered Bispecific Antibodies with Exquisite HIV-1-Neutralizing Activity

Area of Science:

• Immunology
• Virology
• Biotechnology

Background:

• The development of an effective HIV-1 vaccine is ongoing.
• New virus-neutralizing monoclonal antibodies (mAbs) are being explored for passive immunization against HIV-1.
• HIV-1's adaptability necessitates improved antibody designs for clinical use.

Purpose of the Study:

• To engineer and evaluate novel bispecific antibodies for enhanced HIV-1 neutralization.
• To assess the potency and breadth of these bispecific antibodies against diverse HIV-1 strains.
• To determine the in vivo efficacy of these antibodies in preclinical models.

Main Methods:

• Design and construction of engineered bispecific antibodies.
• In vitro neutralization assays using HIV-1 pseudotyped viruses and clinical isolates.
• Evaluation of antibody efficacy in HIV-1-infected humanized mouse models.

Main Results:

• One bispecific antibody, 10E8V2.0/iMab, demonstrated potent neutralization of 118 HIV-1 pseudotyped viruses (mean IC50 of 0.002 μg/mL).
• 10E8V2.0/iMab neutralized 99% of tested clade C HIV-1 isolates, the most prevalent subtype globally.
• In vivo studies showed substantial HIV-1 load reduction and complete protection against viral challenge in humanized mice.

Conclusions:

• Engineered bispecific antibodies represent the most potent and broad HIV-neutralizing antibodies developed to date.
• These antibodies hold significant potential as prophylactic and/or therapeutic agents for HIV-1.
• Further development of these bispecific antibodies could advance passive immunization strategies for HIV-1 control.