What does a successful ADC look like?

A successful ADC is the one that works well in cancer patients with unmet medical needs where current approved therapies either work poorly or patients have become resistant or refractory to them.   An ideal ADC should be highly internalized with high lysosomal trafficking in multiple tumor types with varying degree of the antigen expression. Additionally, it should exert a rapid and sustained tumor killing (either PR or CR) with better tolerability than the chemotherapeutics or radiation treatment or other targeted therapies.  In cancer treatment, combinations of potential cancer therapeutics with different MOAs of tumor killing or disease control is very common.  Ideally, all ADCs could be combined with the agents that have been traditionally combined with cytotoxic chemotherapeutic agents. However, given the low TI, steep threshold for DLTs of the most ADCs, the toxicity remains an important criteria  in deciding which therapies could be combined.  ADCs with good safety and sustained activity following repeated cycles of ADC treatment are the best candidates for combinations with other chemotherapies, targeted agents and radiation.  With the success of immune-oncology agents, including immune checkpoint inhibitors of PD-1:PD-L1 axis, CAR-T cell therapies, it is not surprising that nearly all clinical stage ADCs are being combined with cancer immunotherapy agents to boost the anti-tumor responses.  But it is imperative that mechanism based combinations are employed with ADCs. If the candidate ADC is unable to induce immunogenic cell death or increase tumor mutational burden or activation of the immune system,  it would be counter-intuitive to combine the candidate ADC with cancer immunotherapy agents.

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Rakesh Dixit, Ph.D, DABT
Rakesh Dixit, Ph.D, DABT, 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, he 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, Dixit contributed to the successful filings of many blockbuster drugs. For about a year, he was associated with Johnson and Johnson PRD, La Jolla/Alza as Senior Director of Toxicology. In Aug 2006, Dixit joined AstraZeneca Biologics (formerly MedImmune) to lead Global Biologics Safety Assessment, Experimental Pathology, and Laboratory Animal Medicine. In his current position, Dixit is responsible for providing guidance on research and development of biological products; including nonclinical toxicology/safety support for all AstraZeneca biologics products, including monoclonal antibodies and vaccines. Rakesh Dixit has published more than 60 papers in renowned international journals and has given over 100 invited lectures/presentations/workshops in national and international meetings. His areas of expertise are mainly in the area of pharmaceuticals and biologics drug development, safety assessment of small molecule drugs, biologics, vaccines and in exploring mechanisms of toxicity. He is also considered a recognized expert in safety and pharmacology biomarkers and has won many awards.