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 DuoBodyÒ 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.