Anti-VEGF Antibody Treatment Markedly Inhibits Tumor Growth in SCID-hu Models of Human Multiple Myeloma.

Vascular endothelial growth factor (VEGF) is an important signaling protein that plays a critical role in vasculogenesis and angiogenesis, and serves as one of the contributors to physiological or pathological conditions that can stimulate the formation of new blood vessels. The uncontrolled growth of new blood vessels is an important contributor to a number of pathological conditions, including multiple myeloma (MM). In support of this, bone marrow angiogenesis has been shown to correlate with disease status and poor prognosis in MM. VEGF also directly induces myeloma cell proliferation. Based on these findings, we evaluated a new mouse/human anti-VEGF antibody using our SCID-hu mouse models of human MM. Each immunodeficient (SCID) mouse was implanted with a 2.0 – 4.0 mm³ LAGκ-1A tumor fragment into the left superficial gluteal muscle. The tumors were allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into one of two treatment groups. In one group, anti-VEGF antibody was administered via intraperitoneal injection twice per week at a dose of 5 mg/kg. In the other cohort, control mice were given a control IgG antibody (5 mg/kg) on the same schedule. Mice receiving the anti-VEGF antibody showed marked inhibition of tumor growth (P = 0.0005) and reduction of paraprotein levels (P = 0.0002) compared to mice receiving control antibody. On day 42, LAGκ-1A-bearing mice receiving the anti-VEGF antibody showed a 70% reduction in human paraprotein levels and an 80% decrease in tumor volume compared the control antibody treated animals. Treatment with the anti-VEGF antibody was not associated with any observed toxicity. We are currently evaluating this anti-VEGF antibody in several of our mouse models of human MM and plasma cell leukemia. Based on these data with anti-VEGF monotherapy, we are currently investigating the anti-tumor activity of anti-VEGF antibody plus bortezomib as well as other available anti-MM agents using our in vivo SCID-hu myeloma murine models. Preliminary results are encouraging with single agent anti-VEGF antibody and additional studies may be used to direct the clinical development of anti-VEGF antibody treatment alone and in combination regimens for patients with relapsing or refractory MM.