Evaluation of Clinical PK & Toxicity of Antibody Drug Conjugate

Antibody drug conjugates (ADCs) used in the treatment of cancer are designed to harness the specificity of targeted treatment and combine this with the potent cell-killing of a small molecule. ADCs have complex molecular structures, including the key components of a highly-selective monoclonal antibody (mAb) directed against a target of interest, a potent cytotoxic small molecule (payload), and a linker connecting these two species. This linker is intended to be stable in circulation and only release the payload once the ADC is internalized into cancerous target cells. This construct was designed to provide an improvement over the narrow therapeutic indices of cytotoxic small molecule drugs, theoretically resulting in an improved safety profile of the ADC when compared to systemic administration of the traditional chemotherapy agent.
For most ADCs currently in clinical development, doselimiting toxicities (DLTs) often appear to be off-target, in other words, independent of the target of the ADC. Since the small molecule payloads typically utilize a mechanism of action (MOA) of traditional anti-cancer chemotherapy agents, once the free payload is cleaved from the mAb, it can cause the same typical chemotherapy toxicities, including hematologic and non-hematologic AEs, such as peripheral neuropathy and hepatic toxicity. Many of these off-target AEs ultimately define the DLT of the agent, which in turn often dictates the maximum tolerated dose (MTD) and subsequently the dose used in pivotal studies and eventually clinical practice.
The analysis of PK and Toxicity data have been evaluated by statistical methods to combine and quantify the outcomes of a series of clinical trials in a single pooled analysis. The purpose of the analysis was to summarize the key clinical safety data published for ADCs by payload class, and data permitting, to establish a dose-response model for severe grade toxicity incidence as a function of payload, dose/regimen, and cancer type (solid tumor vs. hematologic cancer).