Peptide-HLA-DQ2 biologics for antigen-specific therapy in Celiac Disease

PROJECT SUMMARY/ABSTRACT Antiger Therapeutics Inc is a biotech company specializing in engineering recombinant human leukocyte antigens (HLA) and membrane proteins. In this SBIR Phase I application, we leverage this expertise to develop targeted immunotherapies for celiac disease (CD), a global health challenge affecting approximately 100 million individuals. As a chronic autoimmune disease, CD poses serious health risks such as malnutrition, anemia, reduced bone density, neurological disorders, and cancers like lymphoma. The current paradigm of CD immunotherapies relies heavily on nonselective immunosuppression, but the associated toxicity limits their long-term use. The most effective management strategy is a lifelong adherence to a gluten-free diet (GFD). However, approximately 30% of CD patients experience persistent or recurrent symptoms due to poor dietary compliance, limited access to GFD, or the complexities of managing refractory CD. Antiger Therapeutics Inc aims to approach CD therapy by selectively targeting the aberrant immune response. A pivotal immunogenetic factor in CD is the HLA-DQ2 membrane protein, which presents deamidated gluten peptides to activate pathogenic T cells and disrupt immune tolerance. Our primary objective is to develop a biologic that specifically blocks the pathogenic T cells recognizing the gluten peptide-DQ2 (pDQ2) complex, thereby safely preventing or reversing CD. Because the pDQ2 complex is difficult to assemble due to the inefficient pairing of DQα and DQβ chains, we will employ novel solutions involving disulfide engineering or producing full-length membrane proteins. Notably, the disulfide bond approach has shown promise in our recent success in generating stable pDQ7-Fc molecules for treating antibody-mediated graft rejection. In Specific Aim 1 of this grant, we will generate dimeric pDQ2-Fc fusion proteins with an inter-chain disulfide bond to stabilize the pDQ2 complex. The Fc portion enables dimerization of the pDQ2 complex in an antibody-like structure. In Specific Aim 2, we will generate pDQ2-Transmembrane proteins on detergent micelles. The transmembrane domains of full- length α and β chains of DQ2 will promote the assembly of pDQ2 complex to be solubilized on micelles. In both aims, we will assess the yield and purity of multimeric pDQ2 proteins and measure their inhibitory effect on the activation of pDQ2-specific T cells. By the end of this Phase I SBIR, we expect to generate one or more candidate proteins with acceptable production yield, purity, and function. The Phase II SBIR will focus on testing candidate biologics in humanized murine CD models, ultimately leading toward an IND submission. Commercially, Antiger intends to collaborate with or license the product to a pharmaceutical company for further development, aiming to tap into the high-demand CD therapeutic market, which is projected to be worth $3 billion by 2030. Moreover, the scalable technology holds promise for addressing other class II HLA- associated autoimmune disorders, such as type 1 diabetes and rheumatoid arthritis.