Development of humanized CD176 antibody for anti-tumor immunotherapy

5^th Asia-Pacific Summit on Cancer Therapy

July 20-22, 2015 Brisbane, Australia

Yi Cao

Posters Accepted Abstracts: J Cancer Sci Ther

Abstract :

Thomsen-Friedenreich antigen (TF) is a carbohydrate epitope (glycotope) sequence Galβ1-3GalNAcα1-R. TF was assigned as CD176 using our monoclonal antibody during the 7th Conference on Human Leucocyte Differentiation Antigens. Through systematic and comparative studies, we found that CD176 is masked by terminal sialylation in adult human normal and benign tissues but it is exposed during tumorigenesis as a tumorassociated antigen. Approximately, 60-80% of carcinomas, leukemia and lymphoma carry CD176 on their cell surface. CD176 is also expressed on some cancer stem cells. In addition, CD176 is functionally involved in the liver metastasis process of tumors and the adhesion of cancer cells to the endothelium. Interestingly, we observed that anti-CD176 antibody induces the apoptosis of leukemic cells. The mechanisms of apoptosis of leukemic cells induced by CD176 antibody may be that CD176 antibody binds CD176 carbohydrate structure on apoptosis-associated glycoproteins such as CD95 and DR4 and then activates apoptotic pathways and results in apoptosis of CD176-positive cells. Normal human sera contain the antibody towards CD176. The presence of naturally occurring anti-CD176 antibodies may represent a mechanism of immunosurveillance against CD176- positive tumor cells. In the animal study, the passive transfer of CD176 anti-serum which reacted only with the tumor-associated CD176 in cancer cells could effectively prolong the survival time of CD176+ leukemia mice and inhibit the growth and spreading of CD176+ leukemic cells in bone marrow, spleen, liver and lung. CD176 antibody treatment could be involved in the following process: (1) CD176 antibody could inhibit CD176+ cancer cells metastasis to bone marrow, spleen, lung and liver through blocking the adhesion of cancer cells to the endothelium and hepatocytes; (2) CD176 antibody could mediate the elimination of CD176+ cancer cells through complement-dependent cytotoxicity (CDC) and/or antibodydependent cellular cytotoxicity (ADCC) performed by natural killer cells, neutrophils and macrophages; and finally (3) CD176 antibody could induce apoptosis of CD176+ leukemia cells. These data provided strong evidence that CD176 antibody-based passive immunotherapy lead to a therapeutic response. Therefore, we developed humanized antibodies specific for CD176 towards therapeutic application.