Antibody-Drug Conjugates: Pharmacokinetic/Pharmacodynamic Modeling, Preclinical Characterization, Clinical Studies, and Lessons Learned

Abstract

Antibody-drug conjugates are an emerging class of biopharmaceuticals changing the landscape of targeted chemotherapy. These conjugates combine the target specificity of monoclonal antibodies with the anti-cancer activity of small-molecule therapeutics. Several antibody-drug conjugates have received approval for the treatment of various types of cancer including gemtuzumab ozogamicin (Mylotarg^®), brentuximab vedotin (Adcetris^®), trastuzumab emtansine (Kadcyla^®), and inotuzumab ozogamicin, which recently received approval (Besponsa^®). In addition to these approved therapies, there are many antibody-drug conjugates in the drug development pipeline and in clinical trials, although these fall outside the scope of this article. Understanding the pharmacokinetics and pharmacodynamics of antibody-drug conjugates and the development of pharmacokinetic/pharmacodynamic models is indispensable, albeit challenging as there are many parameters to incorporate including the disposition of the intact antibody-drug conjugate complex, the antibody, and the drug agents following their dissociation in the body. In this review, we discuss how antibody-drug conjugates progressed over time, the challenges in their development, and how our understanding of their pharmacokinetics/pharmacodynamics led to greater strides towards successful targeted therapy programs.

Fig. 1

Timeline of the US Food and Drug Administration approval of monoclonal antibody therapeutics and antibody–drug conjugates. Antibody–drug conjugates discussed in this review are highlighted with a yellow star. The color of each block denotes the type of antibody: blue, murine; red, chimeric; orange, humanized; green, human. *This timeline only includes therapeutics approved at the time of writing this review (2017). The number of approvals between 2015 and 2017 is in line with the increasing trend in approved biologic therapeutics

Fig. 2

Antibody–drug conjugate (ADC) assembly and interaction with target cells. a Assembly of an ADC. b Typical mechanism of action of an ADC. The administered ADC binds to antigens expressed on the surface of target tumor cells. Following binding, the ADC is internalized. Some of the ADC is recycled back to circulation by the neonatal Fc receptor (FcRn). The remainder of the ADC is trafficked from the late endosome to the lysosome where the antibody is degraded and the linked drug is released. The free drug enters the nucleus of the cell and damages DNA leading to cell death