Session 7, Abstract 42

IDENTIFICATION OF CD206 AS A SPECIFIC MARKER OF TUMOR ASSOCIATED MACROPHAGES FOR USE IN ADEPT TREATMENT OF GLIOBLASTOMAS

Jessica Wada*, MaryAnn Alexander*, Sarah Victor, Jordan Silva, Eric Garcia and Roujih Tadros (Michael I. Dorrell), Point Loma Nazarene University, Dept. of Biology, 3900 Lomaland Dr., San Diego, CA 92106. 

While cancer treatments have advanced substantially, side effects and the inability to deliver adequate chemotherapy to the tumor sites remain. One treatment strategy, Antibody-Directed Enzyme Prodrug Therapy (ADEPT), uses antibodies against tumor-specific antigens to deliver an enzyme that activates a non-toxic pro-drug to its active form at a targeted location. ADEPT has the potential to minimize systemic toxicity and to deliver higher levels of activated drug directly to the tumor. However, identification of tumor-specific markers has been elusive. Rather than targeting the tumor cells, we are targeting non-tumor cells within the tumor microenvironment, specifically, Tumor Associated Macrophages (TAMs). TAMs are responsible for aiding tumor growth and survival in glioblastoma. TAMs have been differentially activated by the tumor microenvironment, eliminating their M1-like phagocytic activity in order to promote M2-like activities, which result in immunosuppressive, pro-angiogenic, and metastatic effects. Our studies have identified CD206 (a.k.a. mannose macrophage receptor or MMR) as a specific, differentially-activated, marker of TAMs within glioblastoma brain tumor sections; it is not expressed by normal residual brain macrophages. This may be a valid target for ADEPT, facilitating antibody-based delivery of a mutated version the human enzyme carboxypeptidase A1 (CPA1) to the tumor microenvironment. This rationally-designed version of CPA1 was designed to specifically activate a correlated methotrexate pro-drug, leading to active methotrexate within the tumor. The overall ADEPT strategy, identification of MMR as a target for ADEPT, as well as current ​in vitro​ efforts to differentiate primary macrophages that express the MMR marker will be discussed.

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