The purpose of this new FOA is to support the optimization of mAb or mAb derivatives that recognize and eliminate cells comprising the HIV reservoir.
Curing HIV infection is a high priority for the NIH. Eliminating the cells that harbor latent HIV proviruses is a major obstacle because these long-lived reservoirs can reactivate and produce infectious virions. Reactivation is not sufficient to kill the provirus-containing cells and immunity, by itself, is also unable to eliminate these reservoirs. Consequently, HIV-infected individuals must remain indefinitely on antiretroviral therapy. With the long-term goal of eradicating HIV infection, or conferring states of antiretroviral-free sustained remission, this FOA will support the optimization of interventions that can eliminate active and reactivating HIV reservoirs.
Monoclonal antibodies (mAb) and mAb derivatives are attractive candidates for reservoir-eliminating interventions: they are exquisitely specific and they can facilitate the killing of cells that express their cognate antigens. Basic research supported in part by the NIH has led to the identification of many mAb specific for HIV envelope glycoproteins. Several HIV-specific broadly neutralizing mAb (bNAb) are being evaluated clinically as means to prevent and treat HIV infection. Results from preclinical studies suggest these bNAb could also play a role in eliminating HIV reservoirs, and exploratory clinical trials are underway. However, the desired mAb characteristics for HIV prevention might not be appropriate or optimized for eliminating HIV reservoirs.
The bNAb currently in the clinic were chosen because they have the capacity to neutralize infectious HIV virions. Since the targets for reservoir elimination are HIV-producing cells, rather than free HIV virions, reservoir-targeting mAb may not require neutralizing activity. Rather, they must bind with high specificity, potency and avidity to cells producing HIV proteins, and then eliminate these HIV-infected cells either by recruiting and activating cytotoxic immune effector mechanisms, delivering cytotoxic payloads, or otherwise causing the infected cells to die. In addition, they will need favorable biodistribution characteristics, as the anatomic locations of all the HIV reservoirs are currently unknown. For example, the antibodies may need to be optimized to penetrate the blood-brain barrier to target central nervous system reservoirs. Like the bNAb in development for prevention, they will also need to be safe and should exhibit long half-lives.
Published studies have described modifications in the Fc region of mAb that increase their ability to mediate cytotoxic activity and extend their half-lives. However, these modifications have yet to be combined with others that improve potency, avidity, breadth, and/or biodistribution. This FOA aims to fill that gap. At the end of the award period, it is anticipated that one or more mAb or mAb derivatives optimized for eliminating active and reactivating HIV reservoirs will be ready for further advancement toward human testing. Specifically, the optimized product(s), either alone or in combination, should exhibit improved potency, avidity and breadth in killing infected cells ex vivo along with evidence of improved efficacy, pharmacokinetics and biodistribution in animal models.
This FOA will support applications that propose hypothesis-driven mechanistic studies aimed at the optimization of mAb or mAb derivatives that recognize and eliminate cells comprising the HIV reservoir. Areas of interest include, but are not limited to:
- Generation of HIV-specific mAb or mAb derivatives with:
- Improved Fab function to increase specificity, potency, avidity and breadth
- Improved Fc effector function to eliminate cells expressing HIV proteins
- Increased half-life and biodistribution
- Studies of polyreactivity, autoreactivity (e.g. cross reactivity to human adult and fetal tissue) and immunogenicity (e.g. anti-antibodies)
- Assessments of pharmacokinetics and efficacy (i.e. capacity of individual products or combinations of products to eliminate active and reactivating HIV reservoirs) in appropriate animal models
For the purposes of this FOA, the following HIV-specific mAb or mAb derivatives are within scope:
- Broadly neutralizing or non-neutralizing mAb
- Bispecific and multi-specific mAb
- mAb conjugated to other proteins, peptides, or compounds
Deadlines: May 16, 2016; January 10, 2017; May 9, 2017; January 9, 2018; May 8, 2018; January 9, 2019
Filed Under: Funding Opportunities