Monoclonal Antibody and Targeted Toxin Therapy

Abstract

Overview Monoclonal antibodies have impacted significantly on the care of patients with cancer. Overall, the US FDA has approved 100 different monoclonal antibodies for the treatment of human diseases. More than 40 monoclonal antibodies, cytotoxic drug conjugates, radionuclide conjugates, and targeted toxins have been approved for the treatment of more than two dozen different malignancies. Useful monoclonal antibodies have most frequently targeted structural proteins and receptors on the cancer cell surface (CD20 by rituximab, HER2 by trastuzumab, and pertuzumab), inhibiting growth, inducing apoptosis, and enhancing chemotherapy, but some have targeted cytokines (IL‐6 by siltuximab), growth factors (vascular endothelial growth factor (VEGF) by bevacizumab), and growth factor receptors (VEGFR2 by ramucirumab) that affect both cancer cells and normal stromal cells including endothelial cells and lymphocytes. Monoclonal antibodies have disrupted checkpoint inhibition of effector T lymphocytes by blocking CTLA4 (ipilimumab), PD1 (pembrolizumab, nivolumab, and cemiplimab), and PD‐L1 (atezolizumab, durvalumab, and avelumab). In the case of trastuzumab and pertuzumab, binding of the two antibodies to different sites on the HER2 cell surface receptor has produced greater antitumor activity than either alone. Enhanced cancer cell killing has also been achieved by conjugation of antibodies with cytotoxic drugs (emtansine to anti‐HER2 trastuzumab and vedotin to anti‐CD30 brentuximab) or radionuclide conjugates ( 90 Y to anti‐CD20 ibritumomab tiuxetan) permitting effective treatment of patients who had failed therapy with unconjugated antibodies. There are several barriers to effective therapy with monoclonal antibodies including antigen specificity, antigenic modulation, heterogeneity of antigen expression, effective delivery of antibodies to cancer cells, potency of effector mechanisms, and response to immunologically foreign globulin. The latter problem has been circumvented with the use of chimeric constructs, humanization of murine antibodies, and developing genetically engineered mice with the ability to develop fully human antibodies. Use of unconjugated antibodies is likely to improve as our knowledge of tumor biology and immunology grows, identifying targets such as OX‐40 ligand. Use of smaller molecularly engineered binding constructs may improve pharmacokinetics and pharmacodynamics of monoclonal antibody and conjugate therapy. Combinations of antibodies may be required to compensate for antigenic heterogeneity. Development of more effective antibody–drug conjugates will require the identification of monoclonal reagents that target tumor‐initiating stem cells. Use of antibody fragments, pretargeting, and the use of alpha‐emitters are promising approaches to improving antibody–radionuclide conjugates. Development of targeted toxins must be further explored.