Antibody-Drug Conjugates: Are “Smart Bombs” Smart Enough?

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By Saurabh Vispute posted 03-22-2018 15:31

  

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The limited number of therapeutic options for several oncological and hematological diseases and recent advances in antibody engineering and conjugation technologies have made antibody-drug conjugates (ADCs) an emerging option for cancer treatment. ADCs have a complex structure comprised of a target‑specific antibody with a linker-based conjugation to a cytotoxic small molecule (warhead).

The successful and well-attended “Nonclinical to Clinical Translation of Antibody-Drug Conjugates” Workshop Session at the 2018 Annual Meeting and ToxExpo highlighted the challenges in nonclinical to clinical translatability of ADCs and regulatory considerations based on ICH S9 (Guidance for Nonclinical Evaluation of Anticancer Pharmaceuticals). Despite technological advances and good preclinical efficacy and potency, off-target toxicities remain a major cause of attrition of ADCs through clinical trials. As highlighted by Subramanya (Subbu) Karanth, MedImmune, in a broad overview of the topic, out of more than 70 ADCs that have been in clinical trials (in Phase I), only four ADCs have been approved to date.

The lack of nonclinical to clinical translatability has been an impediment in predicting or monitoring adverse toxicities. Nicola Stagg, Genentech Inc., shared her experience of developing ADCs with different warheads and dose-limiting toxicities observed in non-clinical setting. Dr. Stagg also discussed the need for a selective nonclinical model or disease model which may help to better predict clinical translatability of nonclinical findings. In addition to specific targeting antibodies, several types of potent cytotoxic small molecules (warheads) have been used in ADCs. The examples presented by Dr. Stagg highlighted certain class effects which may be specific to the type of warhead and reinforced the factors to be considered during species selection and correlations, such as differences in target biology, antigen expression, and pharmacokinetics.

The challenges in ADC development characterized by class effects, on-target versus off-target effects, and linker stability are well-acknowledged, but not completely understood. According to Haley Neff-LaFord, Seattle Genetics, there are several approaches that may be implemented to improve tolerability by antigen selection, site-specific conjugation, effector function changes, physicochemical properties, and ratios of drug-linker combinations. There is clearly no “one size fits all” and tweaking some of these parameters may help improve the safety profile of next-generation ADCs.

Whitney Helms, US Food and Drug Administration, shared concerns about inconsistencies with respect to “more limited evaluation” interpretation of ICH S9 regulatory guidance and the follow-up draft ICH S9 Q&A were discussed. The case studies presented provided perspective on the agency’s interpretation and recommendations for first-in-human dose selection on a case-by-case basis. The remainder of the talk shed clarity on the need for small molecule or total antibody studies in support of ADC studies and the types of additional studies required, such as repeat dose toxicity, genetic toxicology, reproductive toxicology, etc.

In addition to previously discussed strategies and approaches, complementary efforts to improve therapeutic windows and minimize off-target toxicities are also being explored. Specifically, Mary Jane Hinrichs, MedImmune, presented data supporting fractionation weekly dosing versus once every three weeks, an approach to improve safety and decrease toxicities. However, the weekly dosing approach hasn’t necessarily yielded better safety profiles in all cases. Dr. Hinrichs also discussed the need for optimal clinical trial design by implementation of appropriate patient selection strategy based on target expression, as evidenced Dr. Hinrichs sharing of a retrospective evaluation of patient selection, their target expression, and the correlation to the safety profile.

To sum up the session, technological advances and unmet medical needs have significantly invigorated the development of ADCs, and collaborative efforts to refine preclinical and translational strategies to optimize the therapeutic window and decrease the rate of attrition for novel ADCs are underway. As a result, it wouldn’t be incorrect to expect that next-generation ADCs are “smarter” than their predecessors.

This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email SOT Communications Director Michelle Werts.

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