Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens

Executive Summary of Predicate SBIR Phase I Grant and Team Project Title: Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens Organization: GigaMune Inc. PI: Matthew J Spindler, Ph.D. Engineered adoptive cell therapies including chimeric antigen receptor (CAR-T) and T cell receptor (TCR-T) cell

therapies have shown strong clinical responses in cancer patients with five FDA approved CAR-T cell therapies for hematological cancers and numerous TCR-T cell clinical trials ongoing for the treatment of solid tumors. These new drugs have all leveraged engineered cytotoxic T cells and are designed to directly kill cancer cells.

In contrast to cytotoxic T cells, Tregs function to locally suppress immune responses through antigen-specific activity. TCR engineered regulatory T cells (TCR-Tregs) could be used for the treatment of patients with autoimmune disorders, not for killing target cells but rather for preventing cells from being killed. However, in

order to develop engineered TCR-Treg cell therapies, there is a critical need in identifying autoantigen reactive TCRs to specifically direct Treg activity into pancreatic islets where they can locally suppress the autoreactive cytotoxic T cells causing disease pathology. Type 1 diabetes (T1D) autoantigens, including preproinsulin, IA-2, and GAD65, are ideal TCR-Treg cell targets

as they are specifically expressed in pancreatic islets and beta (b)-cells. These autoantigens are commonly targeted by CD4 and CD8 T cells in T1D patients with peptide epitopes presented across many HLA alleles. Importantly, recent studies have demonstrated that TCR clonotypes isolated from CD8+ T cells can redirect Treg

suppressive activity to class I HLA presented peptides. This suggests that engineered TCR-Tregs targeting T1D autoantigens could suppress autoreactive cytotoxic T cells within the pancreatic islets. Therefore, a catalog of TCR-Treg cell therapies targeting T1D autoantigens across different HLA alleles would provide a broadly

effective treatment for T1D patients. The Specific Aim of the R43AI170407 Phase I SBIR project is to develop a catalog of natural human TCRs that target T1D autoantigens for use in TCR-engineered Treg cell therapies. GigaMune's unique technology uses microfluidics, genomics, and mammalian display to generate millions-diverse, natively paired TCRab repertoire

libraries. The TCRab libraries are immortal, enabling repeated experimentation with a panel of antigens. This will expedite discovery of rare anti-T1D TCRs. The project recently started in late 2022 and we have no technical progress to report. After completing this Phase I SBIR project, GigaMune will further develop promising TCRs

as TCR-Treg cell therapies, through in vivo efficacy studies, in vitro safety studies, and manufacturing development. The R43AI170407 I-Corps Supplement is led by GigaMune co-founder Dr. Matthew J. Spindler, an expert in immunogenomics and inventor of the GigaMune technology and supported by GigaMune CEO, serial

entrepreneur, and GigaMune co-founder David Johnson. The industry expert is Jennifer Keller, a trained genetic counselor and marketing manager. Ms. Keller has a broad understanding of potential disease applications, as well as therapeutic market segments. All three team members have previously worked together on NIH I-Corps

projects at GigaGen, which culminated in discovery of a key pharmaceutical development partner (Grifols) which bought GigaGen for $143 million in 2021. The products identified during the course of the prior NIH I-Corps projects are currently under clinical development at Grifols. All three I-Corps team members, having prior experience with the program, understand the significant time

requirements of the program and are committed to success. Like all early stage biotechnology companies, GigaMune is facing an extremely challenging fundraising environment. As such our primary goal in this I-Corps Supplement is to understand the needs of pharmaceutical development partners, so we can partner early,

without further equity financing.