SBIR Phase II: Antibody Therapy that Targets Neoantigens in Acute Myeloid Leukemia by Leveraging Both Innate and Adaptive Immune Mechanisms

The broader/commercial impact of this Small Business Innovation Research (SBIR) Phase II project is centered on a breakthrough antibody immunotherapy for acute myeloid leukemia (AML), with long term curative potential at a fraction (10-25%) of the cost of cellular therapies. As a result, an entirely new category of immunotherapy would emerge to treat a broad spectrum of cancers manifesting “neoantigen” targets that science has unearthed over the last decade. The proposed project will address the inadequate effectiveness of current AML therapies. The project goal is to develop a breakthrough therapeutic platform for oncology in general and AML in particular — as a next-generation antibody immunotherapy that efficaciously leverages both the innate and adaptive immune systems. A combination of two related antibodies will be developed with a shared variable region that binds neoantigen-manifesting cancer cells with exquisite specificity. These antibodies should engage both innate immune cells (e.g. Natural Killer cells) as well as adaptive immune cells (e.g. T cells) — resulting in enhanced efficacy, reduced toxicity, and off-the-shelf availability. Project objectives include creating in silico variants of the 3 distinct antibody candidates from Phase-I of this project, as well as developability testing of the emergent antibody candidates based on antibody stability, their target binding specificity and kinetics, and their in vivo toxicity profile. In vitro functional testing of antibody candidates will quantify antibody potency and effectiveness against patient-derived AML cells. In vivo testing of the top 3 candidate antibodies will be pursued using immunodeficient mice with engrafted human AML disease, and quantified in terms of disease progression and survival — thus forming the basis for the final choice of the lead antibody. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.