Integrin Biology
The cytokine transforming growth factor β (TGFβ) is one of the key mediators in the immune system and has been studied extensively.
Seed, et al. A tumor-specific mechanism of T reg enrichment mediated by the integrin αvβ8, Science Immunology. 2021; 6:8.
Kim, et al. Novel therapies emerging in oncology to target the TGF-β pathway, Journal of Hematology & Oncology. 2021; 14:4.
TGFβ is a multifunctional cytokine involved in many cellular processes, including cell growth and differentiation, immune responses, wound healing, and tissue repair. TGFβ plays a key role in fibrosis and also promotes cancer growth and metastasis via its effects in the tumor microenvironment (TME). The integrins αvβ8 is expressed by cancer cells αvβ8 enables TGFβ to exert its biologic effects by releasing it from its latent complex. The goal of blocking αvβ8 is to inhibit the deleterious effects of TGFβ.
TGFβ is thought to promote growth and metastases of established tumors, inducing immunosuppression, fibrosis, blood vessel growth, and changes in tumor cells themselves. Some tumor cells of human epithelial malignancies express αvβ8, leading to activation of TGFβ in the tumor microenvironment. Overexpression of αvβ8 by tumor cells and expression of TGFβ in tumors has been linked to poor clinical outcomes.
Corbus is developing CRB-601 for treatment of solid tumors in combination with existing therapies.
CRB-601 is an anti-αvβ8 mAb and potent at picomolar concentrations in inhibiting activation of TGFβ. C6D4, the parent mAb of CRB-601, has single agent activity as well as synergistic activity when combined with an anti-PD1 mAb in syngeneic mouse tumor models. CRB-601 was licensed from University of California San Francisco (UCSF) and invented by Dr. Stephen Nishimura and his team.
CRB-601 is being evaluated as a monotherapy in a Phase 1 clinical study for the treatment of solid tumors and will also be studied in combination with checkpoint inhibitors (CPIs). CPIs are drugs that block proteins called checkpoints that are made by some immune systems and cancer cells. Currently, only 44% of cancer patients are eligible for CPIs, and only 12.5% of all treated cancer patients respond. Among patients who respond to CPIs, disease progression often occurs due to resistance mechanisms. Significant unmet need remains for greater and more durable responses to CPIs.
We believe that the combination of CRB-601 and an anti-PD-1 mAb, a type of CPI, has the potential to provide greater and more durable anti-tumor responses than either agent alone.