P3-16-04: A Novel Monoclonal Antibody to Secreted Frizzled Related Protein 2 Inhibits Triple Negative Breast Carcinoma Growth Rate In Vivo.

Abstract

Abstract Background: Secreted frizzled related protein 2 (SFRP2) is a novel angiogenesis factor expressed in the endothelium of a wide variety of human tumors including triple negative breast cancer and angiosarcoma. We previously reported generating a monoclonal antibody against SFRP2 that inhibits endothelial cell and angiosarcoma tube formation in vitro, and decreased tumor volume of the SVR angiosarcoma in vivo. The objectives of these studies were to determine pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the SFRP2 MAb, and evaluate its efficacy in a triple negative breast cancer xenograft. Methods: 125 I-SFRP2 MAb was administered to nude mice i.v. via tail vein injections at 0.4 mg/kg, 4 mg/kg, or 10 mg/kg in mice with or without tumor. Blood organ, and tumor samples were collected at various time points from 5 min to 21 days. Radiolabeled SFRP2 MAb in serum and tissues was determined using a gamma counter. PK parameters were determined based on mean concentration values for 3–5 animals per time point. In vivo efficacy study: MDA-MB-231 human breast cancer xenografts were established in 6-week-old female nude mice. Mice were inoculated with 1 × 106 cells s.c.. Treatment began on day 16 after tumor inoculation when average tumor size was 200 mm3. Animals were randomly assigned (n = 12 per group) to buffer control, SFRP2 MAb 4 mg/kg iv twice weekly; Avastin (Roch) 5 mg/kg iv twice weekly, or IGg control 4 mg/kg iv twice weekly. Tumors were harvested when the tumor diameter reached 2 cm or at 28 days. Tumor volumes were measured with a caliper. Growth rates (percent change per day) were compared with the formula ((Final volume- initial volume)/ initial volume) x 100 / number of days. Differences in growth rate between treated and control were analyzed with a two-tailed t-test. Results: PK and PD: SFRP2 MAb was long circulating in the blood with an average t1/2 in the range of 53–89 hr. In addition, the SFPR2 MAb was found to preferentially target the tumors versus all other organs except for the liver. For example, in tumor bearing mice, the blood/tissue ratio on day 14 was smallest in the liver (15:1) and tumor (16:1) as compared to all other organs (range: 39:1 to 255:1) proving that the tumor was a prime organ for accumulation of the SFRP2 MAb. The SFPRP2 MAb in tumor bearing and non-tumor bearing mice exhibited dose-independent kinetics as a one-way ANOVA analysis comparing t1/2 at different dose levels was not statistically significant (p=0.2847 and 0.1204, respectively). However, there was statistically significant difference in t1/2 of the SFPR2 MAb in tumor-bearing and non-tumor bearing mice (p=0.0386). Efficacy in triple negative breast cancer: There was a 40% decrease in growth rate between SFRP2 MAb and control (p=0.03) and a 20% inhibition of growth rate between Avastin and control (p=0.40). The IgG negative control had no effect on tumor growth. Conclusion: The SFRP2 MAb was long circulating and the tumor was a prime organ for accumulation of the SFRP2 MAb. SFRP2 MAb slowed the growth of a human triple negative breast cancer xenograft in a tumor model that was not sensitive to Avastin. We conclude that SFRP2 is a novel therapeutic target for breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-04.