Glytr Therapeutics, Inc.

EXTENDED?HALF-LIFE?GLYTR1 Combined With Checkpoint Blockade?for Cancer Immunotherapy - Abstract Treatment of Non-resectable Recurrent/metastatic Solid Cancers Is Currently Palliative Only and There Is an Urgent Unmet Need for Novel Mechanisms of Action and Additional Paradigm Shifting Therapeutic Options. Antigen- Targeting Cancer Immunotherapies Such as Bi-specific Antibodies (eg Bi-specific T Cell Engager or Bite’s) Provide a Unique Approach for Cancer Immunotherapy. However, Applying This Therapeutic Tactic to Solid Cancers Has Been Restricted by a Limited Number of Protein Antigens Safe for Targeting. Moreover, Even If Safe Cell-surface Antigens Are Identified, Different Bi-specific Antibodies Will Likely Be Needed for Each Different Antigen/cancer. This Would Greatly Increase Development Time and Costs. Thus, There Remains a Great Need for Additional Safe Antigen- Specific Immunotherapies, Particularly for Those With Refractory/metastatic Solid Cancers Who Have Few Therapeutic Options. Many Cell Surface Cancer-specific Antigens Are Not Proteins But Rather Complex Carbohydrates That Have Limited or No Expression in Normal Tissues. for Example, SS1,6GLCNAC-BRANCHED N- Glycans Constitute a Small Subset of the Complex-type N-glycans Expressed at the Surface of Normal Human Cells But Are Markedly Up-regulated in Diverse Solid Cancers by Driver Mutations in the Receptor Tyrosine KINASE/RAS/PHOSPHOINOSITIDE-3-KINASE(PI3K) Signaling Pathway. Aberrant Over-expression of SS1,6GLCNAC- Branched N-glycans in Solid Tumors Drives RTK Signaling, Tumor Growth, Motility, Invasion, and Metastasis. as Both a Marker and Driver of Many Diverse Cancers, SS1,6 Glcnac-branched N-glycans Provide an Excellent Target for Antigen-specific Immunotherapies. However, an Antibody to SS1,6GLCNAC-BRANCHED N-glycans Has Never Been Generated. to Address This Issue, We Generated a Novel Class of Immunotherapeutics That Readily Target Abnormal Glycan Antigens With High Specificity. We Have Termed This Technology ‘glycan-dependent T Cell Recruiter’ (glytr, Pronounced ‘glitter’). With Funding From the Biden Cancer Moonshot Program of the National Cancer Institute, We Developed and Optimized the GLYTR1 Bi-specific Protein That Binds Both SS1,6GLCNAC-BRANCHED N- Glycans and CD3 in T Cells. the GLYTR1 Bi-specific Protein Induces T Cell-dependent Killing of a Wide Diversity of Solid Cancers in Vitro and in Vivo With EC50’S as Low as ~50 Femtomolar, Yet Does Not Kill Normal Cells or Trigger “on-target, Off-cancer” Toxicity in Humanized Mouse Models. GLYTR1 Is Undergoing Late-stage Ind-enabling Studies and Upon Fda Approval, the Uc Irvine Cancer Center Will Perform a Dose-escalation Phase 1 Clinical Trial in Relapsed/metastatic Solid Cancer. However, as GLYTR1 Has a Short Half-life of ~2.5HRS and Requires Constant Intravenous Infusion, Herein We Propose to Develop a Longer Half-life Version of GLYTR1. We Also Propose to Examine for Potential Additive/synergistic Activity With Checkpoint Inhibitors. Data From This Proposal Will Be Used to Inform Future Clinical Trials Following Confirmation of Safety of GLYTR1 in Our Phase 1 Trial, Namely Whether a Longer Half-life GLYTR1 And/or Co-treatment With Checkpoint Inhibitors Should Be Pursued.