Although very few biomedical HIV prevention options are available at the moment—the only form officially approved by the U.S. Food and Drug Administration is daily oral pre-exposure prophylaxis (PrEP)—plenty of additional methods are being explored, from periodic injections to implants to mRNA vaccines akin to those used against COVID-19. One very active subfield within this area is the development of interventions involving broadly neutralizing antibodies, or bNAbs.
Much of the recent attention around bNAbs for HIV prevention has revolved around a pair of clinical trials called the Antibody-Mediated Prevention (AMP) studies. But while findings from the AMP studies have excited scientists, they’re only one of a wide range of bNAb avenues currently being pursued.
Here’s a beat-by-beat breakdown of where HIV bNAb science currently stands, based on findings and insights shared at the HIV Research for Prevention (HIVR4P) conference earlier this year.
Advances in HIV bNAb Basic Science
An HIVR4P oral abstract session on Jan. 27 addressed the basic science of bNAbs, focusing on the fragment crystallizable (Fc) antibody region, a part of the antibody that activates the immune system by interacting with cellular receptors and complement cascade proteins. Matthew S. Parsons, Ph.D., of Emory University, and Fatima Laher, MBBCh, of University of the Witwatersrand, co-chaired the session.
Ann M. Carias, Ph.D., of Northwestern University, and colleagues investigated the distribution of the bNAbs VRC01 and VRC07-523LS with various Fc modifications in rhesus macaque monkeys following immunization. “They observed that the differently engineered antibodies result in different antibody distributions throughout the body and in tissues,” Laher told TheBodyPro. Their work “could facilitate a new round of preclinical passive antibody administration studies in nonhuman primates to assess the protective potential of broadly neutralizing antibodies with various Fc modifications,” added Parsons.
Behnaz Heydarchi, Ph.D., of Walter and Eliza Hall Institute, and colleagues examined antibodies derived from vaccinated cows. “Heydarchi and colleagues have demonstrated that an anti-HIV bovine monoclonal antibody, with the ability to neutralize a broad array of viral variants, can be modified to contain human Fc regions that confer it with enhanced Fc-dependent functions,” said Parsons. “Future studies will investigate using modified bovine antibodies with HIV-neutralizing activity as components of preventative microbicides or therapeutic cocktails.”
Christiane Moog, Ph.D., of the University of Strasbourg, and colleagues studied regulatory receptors that play an important role immune functions. They found that a genotype of FCGR2A was associated with HIV control independent of HLA-B57 and HLA-B27. “Moog and colleagues have shed light on a potential mechanism of viral control in people living with HIV,” said Parsons.
Doctoral student Samantha Davis, of the Peter Doherty Institute for Infection and Immunity, and colleagues explored how serum immunoglobulin A (IgA) interacts with Fc in HIV-specific bNAbs. “Davis and colleagues showed that plasma IgA antibodies can interfere with the Fc-dependent functions of some broadly neutralizing IgG antibodies in in vitro assays,” said Parsons. “This work raises concerns that the in vivo functions of broadly neutralizing IgG antibodies are susceptible to this IgA effect. Careful consideration may be required to assemble therapeutic antibody cocktails that are not attenuated by plasma IgA.”
Dung N. Nguyen, M.D., of the Uniformed Services University of the Health Sciences, and colleagues explored functional HIV cure using non-neutralizing antibodies (nnAbs) that mediate immunity via Fc receptor (FcR) effector functions, including antibody-dependent cell-mediated cytotoxicity (ADCC). “Nguyen and colleagues developed a new antibody-like molecule, fusing parts of a CD4 molecule with parts of an antibody, to target a part of the HIV envelope which is usually hidden from the immune system. In lab samples, this molecule could bind to HIV-infected cells and neutralize four HIV strains,” said Laher. “These hybrid antibodies have great potential to contribute to efforts to cure HIV,” added Parsons.
Other bNAb Candidates in Development for HIV Prevention
The basic science roundtable also included discussions of several specific bNAb candidates, including the following:
Bispecific bNAbs. Magdalena Sobieszczyk, M.D., M.P.H., of Columbia University Medical Center, addressed engineered bispecific bNAbs, antibodies that bind to two different viral epitopes simultaneously. Developing bNAbs that target multiple epitopes provides an attractive alternative to combining multiple antibodies, a process that entails pharmacologic challenges. A number of bispecific bNAbs are in development, including 10E8.4/iMab, which is being evaluated at the Aaron Diamond AIDS Research Center and is currently in phase 1 clinical study.
Investigational bNAbs 3BNC117 and 10-1074. Marina Caskey, M.D., of Rockefeller University, presented findings on the bNAb combination 3BNC117 and 10-1074, which is being studied for both PrEP and antiretroviral therapy. While bNAb combinations aim to provide superior antiviral coverage, 50% inhibitory concentrations (IC50) against primary isolates are significantly higher than those predicted by the pseudovirus panels commonly used to evaluate neutralization.
In clinical studies, the combination of 3BNC117 and 10-1074 outperformed monotherapy and maintained viral suppression in the absence of antiretroviral therapy for over five months in people with sensitive viruses. Caskey et al found that antibody half-life and antiviral activity are significantly prolonged by the introduction of certain amino acid substitutions in the Fc domain, knows as LS mutations. Such mutations may allow for subcutaneous dosing of the combination every three months.
Investigational bNAb CAP256V2LS. Lynn Morris, Ph.D., of the National Institute for Communicable Diseases in South Africa, summarized the research and development pathway of a very potent bNAb called CAP256V2LS. Preclinical studies of CAP256V2LS led to the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 012 clinical trial program. The 012 program comprises three clinical trials aimed at evaluating CAP256V2LS for HIV PrEP alone or in combination with two other bNAbs, VRC07-523LS and PGT121, among young women in South Africa.
The Clinical March of bNAbs for HIV
Another oral abstract session on Jan. 27 addressed the clinical development of bNAbs. Three of these presentations revisited the AMP studies.
Stephen R. Walsh, M.D., of Brigham and Women’s Hospital, and colleagues investigated different routes of administration of VRC07-523LS—a bNAb discussed above in the context of the CAPRISA 012 clinical trial program.
In the only efficacy studies of bNAb for PrEP (the AMP studies, discussed above), the bNAb VRC01 was administered intravenously (IV). Other options worth exploring are subcutaneous (SC) or intramuscular (IM) administration, which may be preferred by patients. Walsh presented data comparing IV, SC, and IM routes of bNAb administration from the ongoing HVTN127/HPTN087 study. At each dose evaluated, peak and trough concentrations were highest in the IV groups and lowest in the SC groups, with the IM group in between.
Coleen Cunningham, M.D., of Duke University School of Medicine, and colleagues explored the safety and pharmacokinetics (PK) of the VRC07-523LS bNAb combination discussed earlier—this time to prevent infection in infants exposed to HIV in breast milk. In an ongoing open-label study, infants received 80 mg VRC07-523LS SC within 72 hours of birth. Treatment was found to be safe and well tolerated. Cunningham and colleagues identified week 12 as an appropriate time for a second dose in infants with ongoing breastmilk exposure. While the study remains ongoing, the researchers anticipate that VRC07-523LS, administered every three months, may achieve target levels for the duration of breastfeeding.
Doctoral candidate Kun-Wei Chan, of the New York University School of Medicine, and colleagues studied a bNAb that targets a novel part of the third variable (V3) region of the HIV envelope glycoprotein gp120. Strains of HIV are classified into neutralization tiers, ranging from tier 1 (easy to neutralize) to tier 3 (hard to neutralize), based on their susceptibility to bNAbs. While most bNAbs can neutralize only tier 1 viruses, Chan and colleagues isolated a bNAb called M4008_N1 that neutralized about 40% of tier 2 viruses. By elucidating the neutralization mechanism of M4008_N1, Chan and colleagues have helped pave the way for the design of other immunogens targeting this newly identified site of viral vulnerability.
How Do We Build Better bNAbs?
An oral abstract session on Jan. 28 addressed mechanisms for improving the potency and breadth of bNAbs.
Cathrine Scheepers, Ph.D., of the National Institute of Communicable Diseases in South Africa, and colleagues investigated antibody isotype switching as a mechanism to counter HIV neutralization escape. Scheepers and colleagues used longitudinal deep sequencing of an HIV-directed nAb lineage, CAP88-CH06, to identify several co-circulating isotypes (IgG3, IgG1, IgA1, IgG2, and IgA2), some of which exhibit identical variable regions. They found that IgG3 and IgA1 isotypes were better able to neutralize longitudinal autologous viruses and epitope mutants than IgG1. They also found that detrimental class-switch recombination (CSR) events that resulted in reduced neutralization could be rescued by further CSR—a process they called “switch redemption.” Thus, CSR joins somatic hypermutation (SHM) as an additional immunological mechanism to counter viral escape from HIV-specific antibody responses.
To date, vaccine-induced VRC01-class antibodies starting from unmutated precursors have exhibited limited neutralization breadth, particularly against viruses bearing glycan at residue N276 (glycan276), which is present on most circulating strains. Xuejun Chen, Ph.D., of the Vaccine Research Center in Bethesda, Maryland, and colleagues used a humanized mouse model to compare a multi-strain heterologous boost sequential immunization strategy with previously tested strategies. The experimental strategy elicited cross-clade neutralizing serum titers, including against several strains bearing glycan276.
Among the lineages of VRC01-class bNAbs identified from the immunized mice, two neutralized more than 50% of a 208-strain panel. Chen et al conducted mutagenesis and crystal structure analyses that revealed key sites of SHM and mechanisms for surmounting glycan276 to achieve neutralization breadth.
Doctoral student Rebecca T. van Dorsten of the National Institute of Communicable Diseases characterized the high breadth and potency of combinations of single-chain variable fragments (scFv) of HIV bNAbs against a wide range of virus types. Compared to full-size antibodies, the relatively small size of scFv may permit improved diffusion into mucosal tissues and facilitate vector-driven gene expression. Van Dorsten and colleagues tested combinations of five scFv derived from bNAbs CAP256-VRC26.25 (V2-apex), PGT121 (N332-supersite), 3BNC117 (CD4bs), 8ANC195 (gp120-gp41 interface), and 10E8v4 (MPER) for their efficacy against multiple HIV subtypes.
Combinations of scFv showed significantly improved breadth and potency over individual scFv. Among the combinations evaluated, the V2-specific bNAb CAP256.25 and the MPER bNAb 10E8v4 appeared most frequently in the best double and triple combinations and were also more likely to show synergy. Given their size advantage, combinations of scFv show potential for passive immunization.
Doctoral student Bukola Adeoye, of Boston University School of Medicine, and colleagues compared anti-HIV antibody responses among treatment-naive plasma samples from people living with HIV, some of whom were also living with tuberculosis (TB). Those with both HIV and TB had a significantly higher breadth and potency score compared to those with HIV alone. Their results suggest that active TB enhances the neutralizing capacity of anti-HIV antibodies, possibly leading to the emergence of bNAbs that target conserved envelope domains. The mechanism of this synergy remains to be determined, but could ultimately prove valuable in generating a more effective humoral response in HIV vaccination and treatment.
Finally, Emilie Seydoux, Ph.D., of the Fred Hutchinson Cancer Research Center, and colleagues described the development of a novel VRC01-class germline-targeting immunogen derived from anti-idiotypic antibodies. The germline-targeting approach is meant to launch the production of a desired bNAb by stimulating the right antibody-producing cells.
As an alternative to Env-derived germline-targeting immunogens, Seydoux and colleagues developed and characterized a panel of monoclonal anti-idiotypic antibodies (ai-mAbs) that can target and potentially activate putative VRC01-class precursors with high affinity. Their results suggest that ai-mAbs-derived immunogens may have general utility as germline-targeting immunogens against diverse B-cell targets.