Zhu, Zhongyu (NCI)
St. Croix, Brad (NCI)
Seaman, Steven (NCI)
Saha, Saurabh (BioMed Valley Discoveries, Inc)
Zhang, Xaioyan (BioMed Valley Discoveries, Inc)
Welsch, Dean (BioMed Valley Discoveries, Inc)
Decrescenzo, Gary (BioMed Valley Discoveries, Inc)
Angiogenesis is the formation of new blood vessels from pre-existing blood vessels. Angiogenesis occurs during normal growth and development, where it is known as physiological angiogenesis, and during the growth of solid tumors, where it is known as pathological angiogenesis. CD276, also known as B7-H3, is a cell surface tumor endothelial marker that is highly expressed in the tumor vessels of human lung, breast, colon, endometrial, renal, and ovarian cancer, but not in the angiogenic vessels of healthy tissue. This differential expression makes CD276 an attractive target for cancer treatment due to the ability to selectively target pathological angiogenesis without impacting physiological angiogenesis. In fact, CD276-directed therapeutic antibodies may have a higher degree of specificity for tumor vessels than current antiangiogenic agents that cannot distinguish physiological and pathological angiogenesis. Moreover, CD276 protein is also frequently overexpressed on tumor cells. The ability to target the vasculature as well as tumor cells directly makes CD276 a potentially ideal dual-compartment therapeutic target.
Researchers at the National Cancer Institute (NCI) have developed fully human monoclonal antibodies and antibody-drug conjugates (ADCs) that target CD276. The antibodies and ADCs have been tested both in vitro and in vivo and have shown promising data. Pyrrolobenzodiazepine (PBD)-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival in mouse models. In addition, the ADCs have been evaluated in preliminary toxicology studies where they showed limited, if any, off-target toxicity.
- Simultaneously targets both tumor cells and tumor vasculature
- Potentially superior adverse events profile than existing anti-angiogenic agents due to the differential expression of CD276 on tumor and normal vasculature
- Fully human antibodies are less likely to be recognized and cleared by the immune system upon repeated administration.
- Relevance to a wide range of cancers – representing several major market opportunities.
- High cellular internalization.
- Cross-reactive with mouse, rat, and monkey CD276 making preclinical studies easier and more informative.
- Antibody-drug conjugates (ADCs) for the treatment of cancer
- CAR-T cell therapy
- Diagnostic agent for detecting and monitoring CD276-expressing malignancies