Immunogenicity Summit
Immunogenicity and Bioassay Summit

Exclusive Interview with Marjorie Shapiro: Getting FDA Approval for ADCs and Bispecific Antibodies

The 2nd Annual PK/PD of Novel Constructs conference takes place next month on November 11-12 in Washington, DC. The meeting is focused on understanding the metabolism, safety and effectiveness of novel constructs in order to improve their pharmacology, including antibody-drug conjugates (ADCs) and bispecific antibodies. We offer here highlights of the talk that will be given by Marjorie Shapiro, Ph.D., Chief of the Laboratory of Molecular and Developmental Immunology in the Division of Monoclonal Antibodies at the FDA/CDER.

CHI: Can you give some highlights for your talk in November?
Marjorie Shapiro: I’m a CMC reviewer who will speak to an audience that works on non-clinical and clinical PK/PD so I hope to link CMC concerns such as quality attributes with the in vivo properties of the molecules. Quality by design is a multi-disciplinary approach for understanding and defining the target product profile for a given clinical indication. Understanding the quality attributes of the product that will impact the PK/PD of the molecule will improve success of novel constructs.

CHI: Can you speak to trends in submitting bispecific antibodies and antibody-drug conjugates for FDA approval?
MS: The number of IND submissions for all mAbs and related productshas steadily climbed over the last 5-10 years, with huge increases in particular for ADCs as well as a number of bispecific products. There are several bispecific platforms and bispecific antibodies under IND, but none have been approved yet. Once there is an FDA approved bispecific antibody and they are a proven success, the interest with further increase. ADCs are one of the fastest growing segments of mAb related products, and three ADCs have been approved to date with two of the three approved since 2011.For these products to be successful,the cytotoxic drug cannot be released from the mAb too soon, otherwise there will be unacceptable toxicity of the product. Demonstrating the stability of the linker, the affinity of the antibody for the target cell, the pharmacology profile of the cytotoxic drug and the possible activity of the antibody are important considerations.

CHI: What unique challenges do novel constructs present for regulation?
MS: One major challenge in dealing with bispecific antibodies and antibody-drug conjugates is that you may not be able to apply what you’ve learned about effector function and half-life from one molecule to the next. For bispecific antibodies, controlling stability is very important. Target selection and affinity to the target need to be matched so that the antibody arm that binds to the 1st target does not get released before the 2nd target is bound. Developing the relevant potency assays is also a critical challenge. The challenge in regulating ADCs is that they have properties of both small molecule drugs and biologics. Therefore non-clinical and clinical pharmacology studies appropriate for both entities need to be conducted. For CMC, there are2 CMC reviewers, 1 small molecule and 1 biologic reviewer, that work as a team, but overall it requires a more involved regulatory process.

CHI: What advice would you give companies regarding working with the FDA?
MS: Don’t be afraid to ask questions or for clarification if our advice is not clear to you.

CHI: What do you consider some of the most exciting developments for ADCs and bispecifics?
MS: It is exciting to see the diversity of constructs for bispecific and multi-specific antibodies. For ADCs, there are two well established platforms, Seattle Genetics and Immunogen. On the horizon includes new cytotoxic molecules, new linker technologies, and site-specific attachment. There are improvements in controlling the ratio of drug to antibody. Once they can be targeted directly to the site and have an improved risk benefit profile, they may be ready to move into non-oncology indications. Finally, although the focus is on ADCs and bispecific platforms, antibody cocktails should also be included as an exciting development for mAbs and have unique challenges.

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