Abstract 4410: Neutralizing Endosialin antibody, MORAb-004, enhances efficacy of TAXOTERE in a metastatic melanoma model

Abstract

Abstract Endosialin/Tumor Endothelial Marker-1 (TEM1) is a cell surface glycoprotein that is expressed on cells involved in the development of tumor vasculature, primarily pericytes and stromal fibroblasts. Studies have found it to play a key role in tumor growth and neo-vessel formation in numerous cancer types. We are currently evaluating the safety and therapeutic potential of MORAb-004, a humanized monoclonal IgG targeting endosialin/TEM-1, in clinical trials. Because MORAb-004 only recognizes human antigen and has no cross-reactivity with rodent endosialin/TEM-1, we generated a human endosialin/TEM-1 knock-in mouse in order to assess its activity in vivo. Previously, in this transgenic model, we found that MORAb-004 significantly inhibited subcutaneous B16-F10 melanoma progression by ∼70% when administered intravenously for 5 consecutive days. Moreover, using the Lewis Lung Carcinoma model of metastatic disease our results showed that MORAb-004 had a significant inhibitory effect on the number of lung metastases. For these studies, supporting clinical trials for using MORAb-004 in combination with standard of care chemotherapeutics, we developed a B16-F10 melanoma lung colonization model. In this model, the human endosialin/TEM-1 knock-in mice were implanted intravenously with B16F10 cells adapted for in vivo lung colonization. These mice were treated with Docetaxel, MORAb-004, or the combination of the two agents, respectively. A group of the tumor-bearing mice receiving PBS served as control. At the end of the study, the lungs of each mouse were harvested. A ratio of the area of tumor nodules versus total lung surface area is calculated as tumor burden. MORAb-004, at 50 mg/kg three times weekly for a total of 7 i.v. injections reduced tumor burden by 45%. Treatment of Docetaxel, at 3mg/kg twice weekly for a total of 5 i.p. injections, reduced less than 20% of tumor burden in the lungs. When MORAb004 was added to Docetaxel treatment, a significant enhancement of efficacy was observed. The reduction of tumor nodules in the lungs was increased to approximately 70%. A similar trend is seen in combination therapy where MORAb-004 was added to gemcitabine regimen. Our results demonstrate the ability of MORAb-004 to inhibit tumor growth in a murine model. Moreover, when added to the chemotherapeutic regimen, it significantly enhances the therapeutic effect of traditional chemotherapy. 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 4410. doi:1538-7445.AM2012-4410