Analysis of the Efficacy and Cytotoxicity of a Synthesized Anti-HER2 Antibody-Drug Conjugate

Abstract

With biological immunotherapy becoming an increasingly prominent means of treating multiple forms of carcinoma, such immunotherapies are now the focal point of ongoing research. Traditional chemotherapeutic agents are considered cytotoxic in that they interfere with mitosis with the objective of inducing apoptosis in rapidly dividing cells, ideally cancerous cells. Despite the curative intent, there is a concerning lack of specificity of these agents. Healthy cells in the body that normally display increased rates of division are likely to suffer damage consequently. Treatments designed to treat malignant disease target DNA synthesis or replication, mitotic spindles, inhibit protein synthesis or induce cell differentiation.1 The cytotoxic actions of traditional chemotherapies currently used may prove to be effective in some cancer cases, however, such chemotherapeutics are notorious for causing deleterious side effects. Myelosuppression, or reduced production of cells originating from the bone marrow such as erythrocytes, leukocytes, and thrombocytes can manifest as a result. Anemia, immunosuppression, and thrombocytopenia-derived coagulopathy can then respectively ensue.2 It is further documented that known chemotherapeutic agents such as mercaptopurine and azathioprine are associated with myelosuppression, though genetic variation dictates severity.3,4 Developing is an ever-expanding trend to deviate from traditional chemotherapies and pursue more target-based therapies tailored to one’s pathology of disease. The implementation of monoclonal antibodies in the production of antibody-drug conjugates (ADC) is an ideal means of targeting various forms of carcinoma, with the over-arching goal to reduce systemic cell susceptibility to cytotoxic agents. The objective of this work is to produce an ADC to target non-small cell lung carcinoma (NSCLC), that is known to over express the surface antigen human epidermal growth factor receptor-2 (HER2). A monoclonal antibody specific for HER2, trastuzumab, is to be conjugated to a DNA topoisomerase I inhibitor, exatecan. Such an ADC will be tested in vitro against HER2 positive and negative mammalian cells in order to see if this additional element of specificity is effective in inducing cell death selectively.