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Bioanalytical Challenge Themed Issue: Antibody–Drug Conjugates


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Antibody–drug conjugates nonclinical support: from early to late nonclinical bioanalysis using ligand binding assays


Seema Kumar is a Principal Scientist at Pfizer. She leads a group that provides regulated bioanalytical support including assay development, validation and sample analysis for the PK and immunogenicity assessment for preclinical and clinical development of Pfizer’s biotherapeutics portfolio. She is also responsible for scientific oversight of regulated studies outsourced at CROs. Prior to Pfizer, Dr. Kumar held similar role as Director of CLIA certified Clinical Bioanalytical Laboratory at XBiotech USA, Inc. She holds a Ph.D. in Biophysical Chemistry from Johns Hopkins University, and has published several publications in peer-reviewed journals, and contributed to book chapters.


The objective of antibody–drug conjugates (ADC) bioanalysis at different stages of drug development may vary and so are the associated bioanalytical challenges. While at early drug discovery stage involving candidate selection, optimization and preliminary nonclinical assessments, the goal of ADC bioanalysis is to provide PK, toxicity and efficacy data that assists in the design and selection of potential drug candidates, the late nonclinical and clinical drug development stage typically involves regulated ADC bioanalysis that delivers TK data to define and understand pharmacological and toxicological properties of the lead ADC candidate. Bioanalytical strategies and considerations involved in developing successful ligand binding assays for ADC characterization from early discovery to late nonclinical stages of drug development are presented here.


Antibody–drug conjugates (ADCs) are an


emerging class of biotherapeutics that hold potential over conventional chemotherapies to provide targeted delivery of cytotoxic drug to tumor cells with enhanced biologi- cal activity (improved efficacy, selectivity and therapeutic index), and limited systemic exposure. ADCs have complex multicompo- nent structures and are inherently heteroge- neous in nature. The heterogeneity arises due to the different number of small molecule drugs conjugated to the antibody moiety of ADC (also defined as drug to antibody ratio, DAR), and the different sites of conju- gation on the antibody. It is a by-product of conjugation chemistries employed for linking small molecule drugs to the antibody moiety of ADC.


10.4155/BIO.15.107 © 2015 Future Science Ltd The DAR heterogeneity in starting refer-


ence material may evolve further in systemic circulation due to enzymatic or chemical- induced deconjugation of the small molecule drug from the ADC and due to differences in the clearance rate of different DAR spe- cies [1–7]. The physicochemical characteristics of ADCs such as chemistry of conjugation, lability (cleavable vs noncleavable) of the linker, and the actual


sites of conjugation


govern the mechanism of deconjugation, the rate of small molecule drug release and the overall in vivo stability of ADC [1,7]. Owing to their multicomponent struc-


ture, inherently heterogeneous and dynamic nature, multiple analytes are utilized to determine PK and fate of ADCs in vivo [8]. The commonly used ADC-related analytes


Bioanalysis (2015) 7(13), 1605–1617 ISSN 1757-6180 part of


Seema Kumar Author for correspondence: Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global R&D, One Burtt Road, Andover, MA 01810, USA Tel.: +1 978 247 1856 seema.kumar@pfizer.com


Lindsay E King Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global R&D, Eastern Point Road, Groton, CT 06340, USA


Tracey H Clark Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global R&D, Eastern Point Road, Groton, CT 06340, USA


Boris Gorovits Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global R&D, One Burtt Road, Andover, MA 01810, USA


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