Bivalent CD47 Immunotoxin for Targeted Therapy of Lung Cancer

Lung cancer is the leading cause of cancer-related deaths in the world, with ∼2.5 million people diagnosed and ∼1.5 million deaths each year. While the last two decades have yielded substantial progress with systemic targeted and immune therapies improving treatment responses in subgroups of patients with advanced and refractory lung cancer, there is still a dire unmet clinical need to develop more effective therapies with durable responses. CD47 receptors are overexpressed on the surface of a variety of malignant tumor cells including lung cancer. Although there has been increasing interest in developing targeting antibodies against CD47 for immunotherapy, they failed clinical trials due to their dose-limiting toxicities, primarily hematopoietic toxicity. Using a unique diphtheria toxin resistant <i>Pichia pastoris</i> yeast expression system, we have developed a diphtheria toxin-based bivalent CD47 immunotoxin (bi-CD47-IT) for targeted therapy of CD47 ⁺ non-small cell lung cancer (NSCLC). Bi-CD47-IT demonstrated compelling preclinical efficacy in multiple NSCLC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models, including subcutaneous, orthotopic, metastatic and humanized models. This study demonstrates the remarkable preclinical activity of bi-CD47-IT against various lung cancer models, making bi-CD47-IT a novel and promising therapeutic approach for NSCLC.