The Huang Lab's research aims to develop new forms of protective antibodies for HIV prevention and eradication. Using antibody engineering technologies, we focus on generating novel modified antibody-like molecules that have the ability to specifically target and eliminate HIV infected cells, thereby has the potential to eradicate HIV infection.
In collaboration with and in support of ongoing activities undertaken in Dr. David Ho’s lab, the Huang Lab aims to develop effective HIV-1 prevention, control and cure strategies.
Our research focuses on two main areas:
1. Engineering Multi-Specific Antibodies
Previously, we reported an entry mechanism-based strategy to construct HIV-1 receptor or co-receptor anchoring-based bispecific antibodies capable of simultaneously attacking two critical sites involved in HIV entry. We engineered over 200 bispecific antibodies and systematically evaluated their antiviral activity and development potential in vitro. We then used this data to down-select a lead bispecific antibody for in vivo efficacy studies in humanized mice. This research allowed us to identify 10E8.4/iMab, a bispecific antibody candidate that not only has exquisite antiviral breadth and potency, but also favorable product development potential. A first-in-human clinical trial of this bispecific antibody is currently ongoing. 10E8.4/iMab has been engineered to have no Fc-mediated effector function because it has one arm targeting a host-cell protein (CD4). Its anti-HIV effect is to block HIV entry, which may be sufficient for its application as an HIV prevention agent, but it has no ability to kill activated latent reservoir cells that would be beneficial in an HIV treatment setting. With this in mind, we recently expanded our antibody engineering efforts to generate a new panel of bispecific and trispecific antibodies that target different epitopes on the Env protein. We hypothesize that these new multi-specific antibodies could address the limitations of traditional monoclonal antibodies by providing a higher genetic barrier and potentially also benefiting from valiancy contributions. In addition to limiting escape mutant virions from arising, these multi-specific antibodies are also optimized for the killing of Env-expressing cells. The best performing antibody constructs identified by virus neutralization activity and, HIV-1 infected-cell binding and killing will then be evaluated in animal models for their cell-killing capacity, ability to restrict or eliminate latent reservoir cells after activation, and ability to prevent or limit the establishment of the HIV-1 latent reservoir. Using such an approach, we hope to identify multi-specific antibodies that could be applied toward the elimination of latent reservoir cells–one critical component of a multi-pronged approach to HIV-1 eradication.
2. Engineering BI-Specific Based Antibody-Drug Conjugates
Currently available antiretroviral therapies (ARTs) can reduce the level of HIV in blood to an undetectable level. However, current ARTs cannot eliminate the latent reservoirs–a major obstacle to curing HIV-1 infection. Research has found that a number of latency reversal agents (LRAs) are active in vitro but all have little to no impact on the latent reservoir in clinical trials to date. Furthermore, the strategy of increasing LRA doses (in their current forms) is prohibitive, due to the potential for increased systemic toxicity. Thus, it is clear that alternative strategies that specifically targeting and activate the latent HIV reservoir are necessary. We hypothesize that targeted delivery of LRAs to HIV reservoir cells could increase the therapeutic index of LRAs by several orders of magnitude. Our proposal harnesses the exquisite specificity of bispecific antibodies to target the HIV latent reservoir. We will then conjugate a panel of LRAs to promising bispecific antibodies and preferentially deliver them to latently infected cells, minimizing their potential LRA delivery to off-target cells. Currently, we are engineering a panel of bispecific ADCs capable of targeting the narrow subsets of CD4+ resting memory T cells that have been characterized as likely HIV reservoir cells in blood and tissue. Our preliminary results have suggested that the dual targeting/activation strategy is feasible. We will continue to take an iterative approach to assess bispecific ADC binding affinity and avidity, selectivity of LRA delivery, and HIV activation from the latent reservoir in vitro or ex vivo. The ADCs that demonstrate the most promising in vitro or ex vivo properties will be further evaluated for their impact on the latent reservoir in vivo using animal models of HIV infection and treatment.