Recent Advancements in the Use of Antibody Drug Conjugates for Cancer Therapy

Abstract

Monoclonal antibodies (mAbs) have demonstrated considerable utility in the clinical treatment of cancer (Reichert et al. 2005; Reichert and Valge-Archer 2007). While the activities of unmodified mAbs such as Rituxan® (rituximab) in non-Hodgkin’s lymphoma, Panorex® (edrecolomab) in colorectal carcinoma, Herceptin® (trastuzamab) for metastatic breast cancer and Avastin® (bevacizumab) for colorectal and lung cancer are substantial, these agents are rarely curative. As a result, considerable attention has turned to enhancing antibody activity by appending cytotoxic drugs to them, thereby generating antibody drug conjugates (ADCs) capable of site-selective drug delivery. The rationale for this approach is that by delivering cancer drugs to tumor cells, it may be possible to both enhance therapeutic efficacy and spare normal tissues from chemotherapeutic damage. In the past few years, significant progress has been made in this field of research (Damle 2004; Wu and Senter 2005; Kovtun and Goldmacher 2007; Carter and Senter 2008; Chari 2008). Critical parameters for ADC development have been identified which include the choice of target antigen, the ability of the ADC to get localized to target tissues, the fate of the antibody once bound to its cognate antigen, the stability of the linker used to attach the drug to the antibody both in the systemic circulation and inside the target cell, and the potency and mechanism of action of the released drug. Other important considerations include the methods used to generate ADCs, the composition and heterogeneity of the resulting product, and the effects that chemical modification have on such antibody properties as pharmacokinetics, biodistribution, antigen binding and effector functions. This review will describe several aspects of ADC development, with an emphasis on how addressing key parameters have led to promising agents that have advanced into clinical trials.