AR36A36.11.1, a monoclonal antibody targeting CD59, enhances complement activity and exhibits potent in vivo efficacy in multiple human cancer models

A70 Introduction: Activation of complement results in cell lysis through the formation of membrane attack complexes (MACs). CD59 (Protectin), a glycosylphosphatidylinositol-linked protein, is one of a group of complement regulatory proteins that act by blocking MAC formation. It has been suggested that tumor cells over express CD59 to evade complement mediated lysis. Differential expression of CD59 has been observed between normal tissues and several types of cancer including breast, colon and prostate carcinomas. Targeting CD59 with antibodies is therefore a potentially effective therapeutic approach. ARIUS research has created a monoclonal antibody, AR36A36.11.1, which recognize CD59. The in vivo efficacy, epitope and mechanism of action of this antibody has been tested and studied for its potential uses as a cancer drug.
 Method: ARIUS monoclonal antibody AR36A36.11.1 was generated following immunization with human prostate tumor tissue using the FunctionFIRST TM antibody generation platform. Human tumor xenograft mouse models for breast, prostate, lung and colon cancer were used to test the efficacy of AR36A36.11.1. The binding epitope for AR36A36.11.1 was determined by screening synthetic peptides linked to a credit card format chip using PEPSCAN technology. Cytotoxic mechanism of action was determined by measuring the in vitro induction of complement dependent cell lysis.
 Results: AR36A36.11.1 induced cytotoxicity in prostate cancer cell lines and bound to breast, colon, and prostate cancer cell lines. Administered at 20 mg/kg, once per week for 8 weeks, AR36A36.11.1 exhibited potent in vivo efficacy causing tumor growth inhibition of 100% (p in vitro . Development of a humanized form of AR36A36.11.1 has been initiated. Conclusions: AR36A36.11.1 has significant in vivo anti-tumor activity towards a broad range of high incidence cancers. The effectiveness of AR36A36.11.1 may be attributed in part to its ability to block CD59 function as well as enhance complement-mediated lysis. However, the potency of the antibody is maintained at low dose concentrations that do not activate complement cell lysis in vitro . Therefore, complement-independent pathways may play also a role in the efficacy of AR36A36.11.1. Antibody-mediated blockade of CD59 represents a novel approach to cancer treatment.