Wednesday, April 2, 2025
4/2/2025
Tumor-site activated T cell redirecting autoantibodies - Bispecific antibodies have emerged as a promising cancer treatment, with a growing list of encouraging clinical results. Bispecific antibodies enable the binding of two separate targets or the binding of two distinct sites on the same target, simultaneously. This can have important implications when applied as a therapeutic, such as improved specificity and/or unique biological effects. In one common application, bispecific antibodies are designed to physically bring T cells and cancer cells closer together to enhance the immune clearing of cancer cells. Demonstrating the promise of T cell-redirecting bispecific antibodies, blinatumomab, an anti-CD3 x anti- CD19 pair, has produced clinical remission in precursor B cell acute lymphoblastic leukemia at thousand-fold lower dosages than rituximab (anti-CD20 monoclonal antibody), without needing a secondary T cell co- stimulatory signal. In contrast, conventional antibody therapies require cumulative antibody doses ranging from 5-20 g per patient over the course of months to years. Despite the promise of bispecific antibodies (and other immunotherapies), these approaches typically rely on the targeting of a single tumor-associated antigen (TAA) that is over expressed by tumor cells. This can often lead to objective tumor response rates, particularly in solid tumors, since tumor biomarkers are generally not ubiquitously or uniformly expressed by all tumor cells and can be lost during disease progression. To overcome these challenges, we propose to harness a patient’s own anti-tumor autoantibodies, to confer specificity for tumor antigens. Anti-tumor autoantibodies are found within tumors at concentrations that are up to 64-fold higher than normal tissue and evolve with disease progression. Further, there is a rich landscape of recent evidence showing that autoantibodies isolated from tumors are specific to personalized panels of tumor-associated antigens in various cancers, with high clonal and antigen-targeting diversity. This makes autoantibodies well-suited for differentiating between normal and disease pathologies. In our recent work, published in Science Advances, we showed that the transformation of endogenous anti-tumor autoantibodies into highly potent bispecific T cell-redirecting autoantibodies (TRAAbs) can trigger the T cell mediated cytolysis of tumor cells and lead to tumor regression. To our knowledge, this was the first demonstration that increasing the therapeutic efficacy of a patient’s own anti-tumor antibodies offers a viable therapeutic approach; however, a limitation of this approach is the indiscriminate conversion of all serum antibodies into bispecific antibodies, including those with no specificity for the tumor target. The overall goal of this proposal is to engineer a protein therapeutic that limits the transformation of endogenous anti-tumor autoantibodies into highly potent TRAAbs to those antibodies that reside in the tumor microenvironment. The specific aims for this proposal are: Aim 1: Optimize the engineered protein therapeutic to limit TRAAbs to the tumor microenvironment. Aim 2. Determine the distribution and therapeutic efficacy of the engineered protein.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).