Mitigating ADC Toxicities With Linker-Payload Design: De-risking dowstream ADC development by optimizing preclinical assays with PEG-containing linker-payloads.

Antibody-drug conjugates (ADCs) represent the most successful class of active targeting drug-delivery systems, however, despite the increasing number of FDA approvals treatment-related adverse events are common occurrences in the clinical setting and can lead to dose reduction or discontinuation. The overall incidence of adverse events in clinical trials conducted since 2000 was 91% for all grade and 46% for ≥ grade 3, and 84% of clinical trials were terminated in Phase I or II, mostly due to lack of efficacy at the maximum tolerated dose or safety issues. Thus, ADC toxicity remains a major obstacle to ADC development and strategies for mitigation are needed. The standard paradigm for an ADC’s mechanism of action at the site of the tumor is oft-repeated, however it is well-established that less 1% of the administered cytotoxin reaches the tumor and is processed via this route, while the other 99% of the ADC is processed via endogenous clearance mechanisms in other tissues. The properties of the released cytotoxin can also influence activity in the tumor or in other tissues. It is this tug-of-war between ADC processing, and ultimately cytotoxin accumulation and action, in the tumor or in other locations that determines the efficacy and toxicity of an ADC. The different elements of an ADC, including the antibody, the cytotoxin, and the linker can greatly affect partitioning of the ADC and the cytotoxin into the different tissues, and the incorporation of PEG-based components in the linker-payload design is rapidly becoming a common strategy to provide more favorable properties. Optimization of an ADC at the preclinical stage can minimize the chances that insurmountable toxicities arise during downstream development, and this webinar will present use cases where PEGcontaining linker-payload designs have been shown to improve the pharmacokinetic parameters, tolerability, clinical pathology, off-target activity, and non-targeted uptake and biodistribution.

 

Learning Objectives