Efficacy of engineered bispecific neutralizing antibodies against HIV/SHIV infection

Abstract

Human immunodeficiency virus type 1 (HIV-1) is the culprit of acquired immune deficiency syndrome (AIDS). It has caused more than 32 million AIDS-related death and 37.9 million people are living with HIV-1. Traditional antiretroviral therapy can suppress viral replication but cannot eliminate the virus from infected patients. Promising approaches for prevention or treatment become extremely urgent to contain the HIV/AIDS pandemic. The broadly neutralizing antibodies (bNAbs) isolated from HIV-1 infected patients in recent years present great potential to combat HIV-1 infections. However, it remains difficult to induce broad and potent bNAbs by a vaccine. Hence, passive immunization of bNAbs becomes an alternative and promising strategy for prophylactics or therapeutics against HIV/AIDS. Since antibody-resistant viruses easily emerge in single bNAb interventions, I hypothesized that engineered bNAbs, especially bispecific bNAbs (bi-bNAbs), will be more effective in preventing and treating HIV-1.

Passive immunization using bi-bNAbs has not been studied in non-human primate (NHP) models for the prevention of pathogenic simian-human immunodeficiency virus (SHIV) infection and disease progression. Our lab recently demonstrated that the single gene-encoded tandem bi-bNAb, BiIA-SG, is effective against live and diverse HIV-1 infections in humanized mice. Here, to promote its clinical development, I investigated the efficacy of BiIA-SG in Chinese-origin rhesus macaques (CRMs) against the pathogenic CRM-adapted tier-2 R5-tropic SHIVSF162P3CN challenge. Single pre-exposure BiIA-SG injection prevented productive infection in 6/6 CRMs with a lack of proviral load, T cell responses and seroconversion. Single intramuscular BiIA-SG injection, either at 1- or 3-day post-challenge, significantly reduced and postponed peak viremia with undetectable viremia in 8/13 CRMs three months after infection. Importantly, BiIA-SG prevented disease progression in all treated CRMs, as compared to 6/8 simian-AIDS in untreated CRMs. Mechanistically, besides direct neutralizing effects, BiIA-SG treatment promoted the induction of protective CD8+ T cells in controller CRMs as determined by anti-CD8β antibody study. These findings demonstrate the efficacy of the first bi-bNAb in macaques and warrant clinical investigation of BiIA-SG for HIV-1 prevention and immunotherapy.

As HIV-1 transmission mainly occurs via unprotected sexual contacts, it is critical to delivering the preventive bNAbs to the anatomic site of viral entry. Previous studies demonstrated the protective efficacy of passive immunized or vaccine-induced IgA, but the protective efficacy of bispecific broadly neutralizing IgA has not been studied yet. Since BiIA-SG displayed great breadth and potency, I constructed the IgA1 and IgA2 isotypes of BiIA-SG, named BiIA-IgA1 and BiIA-IgA2, respectively, and investigated the in vitro bioactivity and protective efficacy of BiIA-IgA in the HIV-1/NSG-huPBMC mouse model. BiIA-IgA1 and BiIA-IgA2 displayed comparative epitope binding and neutralizing activities compared with parental BiIA-SG. The half-lives of BiIA-IgA1 and BiIA-IgA2 were shorter than BiIA-SG, but they still provided partial protection of NSG-huPBMC mice against HIV-1JR-FL intraperitoneal infection. Furthermore, BiIA-IgA, especially BiIA-IgA2, showed better prophylactic efficacy than BiIA-SG against HIV-1JR-FL intravaginal and intrarectal challenges, respectively, indicating the potential advantage of IgA2 over IgG for mucosal protection as they showed equivalent neutralizing activity in vitro. This study provides supportive evidence for further investigation of the preventive efficacy of BiIA-IgAs against HIV-1 infection.