Q. What are the best strategies to improve the Therapeutic Index (TI) with ADCs?
While the TI in preclinical studies has seen improvement, a good TI in clinical studies in cancer patients remains a major challenge. This is why getting a good therapeutic index in cancer patients remains the Holy Grail of the ADC development. The best strategies involve the improvement in the target delivery to tumors while reducing the normal tissue uptake. Some of the strategies, include better linkers (cleavable and non-cleavable), site-specific conjugation, extending the half-life of ADCs, nanomedicine and personalized medicine approaches etc..
Q. What are the biggest challenges for developing efficacious ADCs?
The off-target toxicities of ADCs remain a major road block in achieving good TI. Efforts are being made to reduce both on and off-target toxicities of ADCs. Some efforts have included a better selection of tumor target antigens, antibodies that are fit-for-purpose for well-behaved ADCs and using precision medicine approaches to minimize the toxicities.
Q. How is treating solid cancers different from other types?
Heme tumors have traditionally yielded the best efficacy for ADCs because of an easier in vivo access to systemic ADCs. Also, many heme tumors tend to be highly sensitive to cytotoxic chemotherapeutics. In contrast, the bulky solid tumors pose the greatest challenge to ADC delivery. There are a large number of acquired mechanisms (e.g., abnormal angiogenesis, high interstitial pressure, harsh tumor microenvironment) in solid tumors that reduce the uptake of ADCs and many solid tumors develop resistance against the cytotoxic warheads and often mutate the target antigens to impede ADC entry.
Q. What are you most looking forward to at this year's PepTalk?
Networking with expert in ADCs, learning the latest developments in ADCs, antibodies and peptides etc.
Rakesh Dixit, Ph.D., DABT, Vice President, Research & Development, and Global Head, Biologics Safety Assessment, Medimmune (A member of AstraZeneca Group)
Dr. Dixit conducted extensive graduate and post-graduate training in Toxicology–Biochemistry with both Indian and US Institutions and is board certified in Toxicology from the American Board of Toxicology, Inc. since 1992. In December 1992, Rakesh joined the Department of Safety Assessment, Merck and Co., Inc, West Point, PA where he served in various management positions. During his about 14 years with Merck, Rakesh contributed to the successful filings of many blockbuster drugs. For about a year, Rakesh was associated with Johnson and Johnson PRD, La Jolla/Alza as Senior Director of Toxicology. In Aug 2006, Rakesh joined MedImmune, Inc. (an AstraZeneca Biologics company) to lead Global Biologics Safety Assessment, Experimental Pathology, and Laboratory Animal Medicine. In his current position, Rakesh is responsible for providing guidance on research and development of biological products; including nonclinical toxicology/safety support for all AstraZeneca-MedImmune biologics products, including monoclonal antibodies and vaccines. Rakesh has published more than 60 papers in renowned international journals and has given over 100 invited lectures/presentations/workshops in national and international meetings.