Semaphorin Proteins as Anti-Angiogenic Therapeutics
Inventors: Michael Klagsbrun, Shay Soker, Seiji Takashima, Harry Miao
Neuropilins (NRP1 and NRP2) are receptors for the VEGF family of angiogenesis factors and for the class 3 semaphorin family (SEMA3A through SEMA3F) of secreted axonal guidance proteins. The proangiogenic effects of NRPs have been typically ascribed to their interactions with VEGF. However, it has come to light that semaphorins, in addition to their neuronal functions, affect the vasculature in an inhibitory manner. The SEMA3F gene is commonly deleted in lung cancer, suggesting that semaphorins might be tumor suppressor genes. Dr. Klagsbrun and colleagues have shown that SEMA3F is lost in highly metastatic prostate, bladder and melanoma cell lines, and that it is a potent inhibitor of angiogenesis, tumor growth in vitro and in vivo, tumor cell adhesion and migration, and metastasis.
The discovery by Dr. Klagsbrun's laboratory indicate that SEMA3F may be a novel anti-angiogenic and anti-metastatic therapeutic for cancer, for example for melanoma and for prostate cancer, alone or in combination. Although several other agents are approved and in development for various oncology indications, there remains an unmet need for effective and well-tolerated drugs and we believe that SEMA3F has several advantages.
Since SEMA3F is a naturally occurring protein, it may show decreased toxicity and may have advantages receiving FDA approval. Results to date suggest that it would shrink the primary tumor and exhibit anti-metastatic activity. Since it is lost in metastatic tumor cells, SEMA3F could serve as a DNA-based biomarker to identify patients likely to benefit from this therapy. The mechanism by which SEMA3F acts is well understood and reliable assays for biochemical activity are available. An anti-NRP1 antibody from Genentech (technology licensed from Dr. Klagsbrun's laboratory) is in Phase 1 in oncology. It blocks VEGF but also SEMA3 binding, thereby potentially counterbalancing the anti-angiogenic activity of the semaphorins. On the other hand, SEMA3F specifically uses NRP2 to exert its effects and may even compete with VEGF. Both of these elements may translate to reduced toxicity and increased effectiveness for SEMA3F as a therapeutic for cancer.
This technology was the recipient of a CHB Technology Development Fund Award in 2009.
Key Publications: Shimizu et al., J Biol Chem. 2008 Oct 3;283(40):27230-8; Bielenberg et al., J Clin Invest. 2004 Nov;114(9):1260-71.
IPStatus: Pat. Pend.