Abstract
Abstract Vaccinex is developing VX15/2503, a humanized IgG4 anti-Semaphorin 4D (SEMA4D; CD100) antibody with approximately 5 nM affinity, for the treatment of patients with advanced solid tumors and for the treatment of patients with multiple sclerosis. SEMA4D is an important mediator of axonal growth cone guidance, angiogenesis, and T cell and B cell activation. Cellular SEMA4D (cSEMA4D) is expressed most abundantly on T cells and to a lesser extent on other lymphocytes as a 150 kDa transmembrane protein. SEMA4D is less abundantly present in serum as a 240 kDa, homodimeric soluble protein (sSEMA4D). VX15/2503 recognizes a discontinuous epitope in the homodimerzation domain of both the cellular and soluble forms of SEMA4D. This epitope is also located on the margin of the plexin B1 (PLXNB1) binding domain, the high affinity receptor of SEMA4D. Binding of SEMA4D by VX15/2503 blocks the binding of SEMA4D to PLXNB1 and reduces cSEMA4D by promoting internalization of approximately 60% over 24 hours. Evaluation of VX15/2503 or its murine progenitor (MAb 67-2) demonstrated that these anti-SEMA4D antibodies suppressed tumor growth, metastases and angiogenesis in syngeneic, xenograft, and transgenic tumor models. Single dose and one month toxicology studies utilizing VX15/2503 were performed in Sprague Dawley rats and cynomolgus macaques at doses of 0, 10, 30, or 100 mg/kg/dose. The no observed adverse effect level (NOAEL) in each study was determined to be 100 mg/kg/dose. A pivotal 6-month chronic dose study in rats is ongoing. Rats are being administered 26 weekly doses of VX15/2503 at 0, 30, 100, or 200 mg/kg/dose; data through 13 weeks have been analyzed. T cell associated SEMA4D remained saturated throughout this phase in mid and high dose animals. On average, high dose rats had a Cmax of 4,378 μg/mL and exposure of 330,878 μgαhr/mL (AUC0-168). Appetance, bodyweight, serum chemistry, behavior, general condition, and ophthalmologic parameters were unaffected by VX15/2503 administration. Treated animals mounted appropriate IgG response; however, low and high dose females produced a slight, but statistically significant lower IgM response than control animals five days following KLH administration. A statistically significant reduction of 33 to 80% was observed in circulating NK cell levels; no similar reduction was observed with macaques dosed weekly X 5 at 100 mg/kg or in ongoing clinical analyses of NK cell levels. Additionally, fewer splenic germinal centers and reduced lymphocyte infiltrates in hepatic parenchyma were observed in the tissues from high-dose animals. These pharmacologic effects did not result in frank toxicity in these animals. A Phase I trial with VX15/2503 is currently being conducted in adult patients with advanced solid tumors. A better understanding of antibody-antigen interactions as well as the nonclinical safety and pharmacology of this antibody will inform clinical development of VX15/2503. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 936. doi:1538-7445.AM2012-936
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