Project Grant R42CA285234

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.