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Mitigating ADC Toxicities With Linker-Payload Design

Webinar — Mitigating ADC Toxicities with Linker-Payload Design

De-risking downstream 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, receiving increasing numbers of FDA approvals. However, treatment-related adverse events are common occurrences in the clinical setting, with 84% of clinical trials terminated in Phase I or II since 2000. This is 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 oft-repeated paradigm for ADC function is that the mechanism of action occurs at the site of the tumor, but in reality, less than 1% of the administered cytotoxin reaches the tumor. The other 99% of the ADC is processed via endogenous clearance mechanisms in other tissues. Thus, cytotoxic effects can occur in either the tumor or other tissues. This means that the efficacy and toxicity of an ADC are determined by its ability to balance being effective in tumors without delivering the same therapeutic effects to healthy tissues.  

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. The incorporation of PEG-based components in the linker-payload design is rapidly becoming a common strategy to provide more favorable properties.  

This webinar presents cases where PEG-containing linker-payload designs have been shown to improve the pharmacokinetic parameters, tolerability, clinical pathology, off-target activity, and non-targeted uptake and biodistribution. Optimize your ADC at the preclinical stage and minimize toxicities during downstream development.

Within the webinar, we have explored:

  • While ADCs are often described as delivering cytotoxic payloads directly to tumor sites, 99% of ADC processing occurs in other tissues.
  • Cytotoxin accumulation in non-tumor tissues can result in toxicity and adverse events in preclinical and clinical trials.
  • Linker-payload designs incorporating PEG moieties can improve ADC performance in preclinical assays, leading to greater success in downstream development.

Speaker:

Matt Giese
Matthew Giese

Senior Scientist, Vector Laboratories

Dr. Giese is a Senior Scientist at Vector Laboratories and has worked in both large pharmaceutical companies and small start-ups. Matt holds a BS in Chemistry from the University of Wisconsin-Parkside, specializing in physical and inorganic chemistry, and an MS in Physical Chemistry and Materials Science from Florida State University. He has industry experience at Roche Diagnostics, where he developed lateral flow immunoassays, marking his first foray into bioconjugates. After earning a second MS in Organic Chemistry from Indiana University-Purdue University Indianapolis, Matt worked at Eli Lilly in Discovery Chemistry, focusing on medicinal chemistry and drug development. He later contributed as an analytical chemist and natural product scientist at NaPro Research. Currently, Matt is a Senior Scientist at Vector Laboratories, where he focuses on bioconjugation, crosslinkers, fluorescent labels, and bifunctional chelators.

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