Class II Human Leukocyte Antigen biologics for antibody-mediated graft rejection.

Antiger Therapeutics Inc., St Louis MO

Investigators

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Abstract

PROJECT SUMMARY/ABSTRACT The mission of Antiger Therapeutics Inc. is to develop novel immunotherapies for transplant recipients to improve long-term graft outcomes and minimize adverse effects. Antibody-mediated rejection (AMR) is a leading cause of graft loss, with over 3000 new cases per year in the United States and estimated market size of $90 million. However, this estimate is likely to underestimate the market potential as currently no FDA- approved drugs or treatments are available for AMR. Donor-specific antibodies (DSA) against class II human leukocyte antigens (HLA) are the most frequent driver of AMR, which was reported in 68-91% of AMR after kidney, heart, or lung transplants. Current therapies, such as plasma exchange and inhibition of all B cells or plasma cells, have not demonstrated benefits for patients with AMR in randomized clinical trials. These therapies also non-selectively suppress the immune system and increase the risk of severe infections. To address these unmet needs, this SBIR will explore antigen-specific depletion of DSA-producing cells as a novel approach to AMR treatment. In our preliminary work, we generated class I HLA fusion proteins that potently and selectively depleted class I HLA-specific target cells in vitro and in vivo. This work motivated us to develop targeted immunotherapies for AMR caused by class II DSA. The product of this SBIR will be a soluble class II HLA biologic, capable of depleting a unique and more precise therapeutic target—B cells producing antibodies against the specific class II HLA expressed on the graft. The technical innovation of this product is the structure-based engineering of class II HLA to stabilize a high-risk antigen in AMR for production and clinical translation. The product will be among the first-in-class biologics to enable antigen-specific immunotherapy on the AMR market, with the potential of prolonging the graft survival and preserving the rest of the humoral immunity for infection control. We hypothesize that functional class II HLA biologics can be efficiently produced through two distinct engineering approaches, and these biologics should demonstrate selective cytotoxicity against B cell hybridomas of the corresponding specificity. In Specific Aim 1, we will generate a monovalent class II HLA biologic to deplete specific antibody-producing B cell hybridomas. In Specific Aim 2, we will create a bivalent class II HLA biologic to deplete target cells. By the end of this phase I SBIR, we expect to generate one or more candidate proteins with high production yield, purity, and selective cytotoxicity against target cells to meet pre-specified acceptance criteria. We will further demonstrate the efficacy and safety of these candidates in vivo in a phase II SBIR and then pursue licensing the product to a pharmaceutical partner for development toward FDA approval. The ultimate therapy, as a result of this project, will shift the paradigm in AMR treatment to antigen-specific immunosuppression with unprecedented precision.