Antibody – VX15 Oncology
SEMA4D (CD100) is a potent pro-angiogenic molecule. SEMA4D signaling through plexin-B1 (PLXNB1) induces activation and migration of endothelial cells resulting in the formation of new blood vessels promoting tumor growth in vivo (REF 1,2). SEMA4D is over-expressed in a wide array of tumor types, and is also produced by inflammatory cells present in the tumor microenvironment. It has recently been demonstrated that in an environment lacking SEMA4D, the ability of mouse breast cancer cells to originate tumor masses and metastases is severely impaired (REF 3).
In addition to its effects on endothelial cells, Sema4D enhances Plexin-B1-mediated transactivation of c-Met that is co-expressed on tumor cells (REF 4-6). It has been reported that overexpression of Plexin-B1 together with Met in prostate and breast cancers is a negative prognostic factor (REF 7,8). Plexin-B1 can mediate both pro-oncogenic and anti-oncogenic signals depending on mutations in functional domains and which membrane receptor kinases are co-expressed on a tumor cell. A high frequency of mutations in Plexin-B1 that enhance oncogenic activity has been reported in prostate cancer.
Collectively, these results suggest that expression of SEMA4D, either by cancerous cells or by tumor associated macrophage, is a widely used strategy by tumors to induce angiogenesis and tumor invasion, thereby enhancing their growth, survival, and metastatic potential. Antibody neutralization of SEMA4D to block its interaction with PLXNB1 receptor may represent a new and effective therapeutic strategy for cancer treatment.
We have selected a high affinity human IgG4 antibody that is specific for both mouse and human SEMA4D, and demonstrated in vitro that this antibody blocks the interaction of SEMA4D and PLXNB1. Using tumor models in mice we demonstrated that antibody mediated SEMA4D neutralization in vivo inhibits tumor growth and vascularization.
A phase I clinical trial of VX15/Anti-SEMA4D antibody for cancer began in January of 2011.
Figure 1. SEMA4D is highly expressed in a wide variety of tumor cells. The bar graph summarizes the data from Sema4D staining in tumor tissue arrays. Between 37.5% and 85.4% of oral, prostate, colon, breast, and lung carcinomas analyzed exhibit moderate to strong Sema4D expression. This figure can be found in REF 2.
Figure 2. (A) The mouse tumor line CT26 was tested for its growth rate in mice either missing (-/-) or containing (WT) SEMA4D. CT26 cells were injected into mice and measured for its growth rate. The data demonstrates that tumors grew slower in mice lacking SEMA4D suggesting that SEMA4D contributes to tumor cell growth. (B) The anti-SEMA4D antibody 67-2 was tested for its ability to inhibit the growth of CT26 tumors. Tumor bearing mice were divided into two groups of 24 mice each, and treated weekly with 1.0 mg of MAb 67-2 or an irrelevant mouse antibody. The data demonstrate that treatment with antibody 67-2 slowed the growth of tumors in these mice. Treatment with antibody 67-2 resulted in a 24% tumor growth delay (logrank results were significant (P < 0.05)). Similar results were observed in four other experiments, including one independent study performed at Piedmont Research Center.
Figure 3. The anti-SEMA4D antibody VX15 was successful in inhibiting the growth of HN6 head and neck tumors in mice. Tumor bearing mice were divided into four groups of 10 mice each, and treated weekly with 1.0 mg of an irrelevant mouse antibody, VX15, anti-VEGF, or a combination of VX15 and anti-VEGF. The data demonstrate that treatment with VX15 alone slowed the growth of tumors in these mice. In addition, an additive effect was seen when used in combination with anti-VEGF. Treatment with VX15 alone resulted in a 29% tumor growth delay (logrank results were significant (P < 0.0001)). Photographs of tumors extracted after study termination support in vivo measurements.
VX15/2503 - Vaccinex is currently conducting a Phase I clinical trial of VX15/2503 monoclonal antibody in adult patients with advanced solid tumors. This is a dose-escalation trial measuring safety and tolerability and to determine the maximum tolerated dose. For further information and eligibility criteria, please refer to the National Institutes of Health ClinicalTrials.gov Web site listed below.
Clinicaltrials.gov VX15 page