Project Grant R43CA285040

CD3 BISPECIFIC FOR THE TREATMENT OF ROR2-POSITIVE NSCLC - PROJECT SUMMARY WE ARE DEVELOPING A NOVEL CD3-BISPECIFIC ANTIBODY PRODUCT, TB-BS1, FOR THE TREATMENT OF LUNG CANCER. LUNG CANCER IS THE LEADING CAUSE OF CANCER DEATHS IN BOTH MEN AND WOMEN IN THE U.S. EACH YEAR, WITH NON-SMALL CELL LUNG CANCER (NSCLC) MAKING UP THE MAJORITY OF CASES. NSCLC ALSO HAS ONE OF THE LOWEST SURVIVAL RATES, WITH 5- YEAR SURVIVAL FOR NEW DIAGNOSES AT ONLY 18%. TREATMENT OPTIONS REMAIN RELATIVELY UNCHANGED OVER THE PAST DECADE, DESPITE THE EMERGENCE OF NEW IMMUNOTHERAPIES SUCH AS CHECKPOINT INHIBITORS AND CAR-T CELL THERAPY. THE SUCCESS OF THESE MODALITIES IS HETEROGENEOUS AT BEST, LARGELY DUE TO THE COMPLEXITY OF THE TUMOR MICROENVIRONMENT (TME). SPECIFICALLY, ON-TARGET OFF-TUMOR TOXICITY AND REDUCED IMMUNE STIMULATION WITHIN THE TUMOR HAVE LIMITED IMMUNOTHERAPY SUCCESS. THEREFORE, EXPLORATION OF NEW TARGETS AND THERAPEUTIC MODALITIES THAT CAN SPECIFICALLY AND POTENTLY DIRECT IMMUNE-MEDIATED CANCER CELL DEATH AT THE TUMOR SITE WOULD PROVIDE NSCLC PATIENTS WITH A MUCH-NEEDED OPTION. HEREIN THIS PHASE I APPLICATION, WE ARE ADVANCING TB-BS1 THROUGH PRECLINICAL PROOF-OF-CONCEPT IN VIVO STUDIES IN NSCLC. TB-BS1 IS BUILT ON THE FC-INERT CD3 DUOBODYO BISPECIFIC ANTIBODY PLATFORM AND HAS A UNIQUE TUMOR ASSOCIATED ANTIGEN (TAA) TARGET, RECEPTOR TYROSINE KINASE ORPHAN RECEPTOR 2 (ROR2). ROR2, A WNT SIGNALING MEMBRANE RECEPTOR THAT IS EXPRESSED AND ACTIVE DURING EMBRYOGENESIS BUT IS ABSENT FROM HEALTHY TISSUES IN ADULTS, IS A NEW TARGET THAT HAS YET TO BE VALIDATED. WE PRESENT HERE A HIGHLY SPECIFIC ANTI-ROR2 ANTIBODY THAT IS BUILT ON A CLINICALLY VALIDATED BISPECIFIC PLATFORM. WE WILL FIRST DETERMINE ROR2 EXPRESSION IN A PANEL OF NSCLC TUMORS AS WELL AS IN NORMAL HUMAN TISSUE SAMPLES. THEN WE WILL EVALUATE THE ANTI-TUMOR THERAPEUTIC EFFECT OF TB-BS1 IN A PROOF-OF-CONCEPT ROR2-POSITIVE NSCLC HUMANIZED MOUSE MODEL. THESE RESULTS WILL SUPPORT THE LAUNCH OF TB-BS1 INTO FULL-SCALE PRECLINICAL DEVELOPMENT FOR THE TREATMENT OF ROR2-POSITIVE NSCLC IN A FUTURE PHASE II APPLICATION.