Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper

Kraynov, Eugenia; Kamath, Amrita V.; Walles, Markus; Tarcsa, Edit; Deslandes, Antoine; Iyer, Ramaswamy A.; Datta‐Mannan, Amita; Sriraman, Priya; Bairlein, Michaela; Yang, Johnny; Barfield, Matthew; Gao, Xiao; Escandón, Enrique; Wang, Weirong; Rock, Dan A.; Chemuturi, Nagendra V.; Moore, D. J.

doi:10.1124/dmd.115.068049

Cited by 80 publications

(67 citation statements)

References 31 publications

(44 reference statements)

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“…Therefore, often a combination of ELISA and LC-MS/MS are used to quantify the payload, mAb, possibly the linker (e.g., if novel or first-in-class), linker-drug combination, and ADC levels in the systemic circulation during preclinical and clinical development . Other drug metabolism-related experiments, such as reaction phenotyping, passive/active transport, cytochrome p450 inhibition/induction, plasma protein binding, and in vitro plasma or serum stability, should be considered on a case-by-case basis (Kraynov et al 2016). In addition to safety assessment studies (Donaghy 2016), an immunogenicity screening assay to detect anti-drug antibodies (ADAs) using an appropriate assay cut-point, domain specificity characterization, and a neutralizing Ab assay need to be designed and validated (Hock et al 2015).…”

Section: Production and Characterizationmentioning

confidence: 99%

Antibody drug conjugates

Bakhtiar

2016

Biotechnol Lett

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Antibody drug conjugates (ADCs) have emerged as a viable option in targeted delivery of highly potent cytotoxic drugs in treatment of solid tumors. At the time of writing, only two ADCs have received regulatory approval with >40 others in clinical development. The first generation ADCs suffered from a lack of specificity in amino acid site-conjugations, yielding statistically heterogeneous stoichiometric ratios of drug molecules per antibody molecule. For the second generation ADCs, however, site-specific amino acid conjugation using enzymatic ligation, introduction of unnatural amino acids, and site-specific protein engineering hold promise to alleviate some of the current technical limitations. The rapid progress in technology platforms and antibody engineering has introduced novel linkers, site-specific conjugation chemistry, and new payload candidates that could possibly be exploited in the context of ADCs. A search using the Clinical Trial Database registry ( www.clinicaltrials.gov ), using the keyword 'antibody drug conjugate', yielded ~270 hits. The main focus of this article is to present a brief overview of the recent developments and current challenges related to ADC development.

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Section: Production and Characterizationmentioning

confidence: 99%

Antibody drug conjugates

Bakhtiar

2016

Biotechnol Lett

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“…ADC bioanalysis was also outlined in a recent industry white paper on ADME (Absorption, Distribution, Metabolism, Excretion) characterization of ADCs [4] and a review of ADC analytical characterization by mass spectrometry [5]. It is fair to say that all literature and conference discussions and evolution on ADC bioanalysis in recent years have been around the topics of selection of analytes, DAR characteristics of the assay, and choice of assay platform (LBA or hybrid).…”

Section: Affinity Capture Lc-ms Measurement Of Intactmentioning

confidence: 99%

Current status of antibody-drug conjugate bioanalysis

Wang¹

2017

J Appl Bioanal

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Keywords: antibody-drug conjugate bioanalysis, ligand-binding assay, hybrid ligand-binding/LC-MS assay, drug-toantibody ratio Antibody-drug conjugate (ADC) consists of a cytotoxic drug covalently bound to a monoclonal antibody via a linker. Because of the complexity of ADC structure unique bioanalytical strategies are needed to identify, characterize and quantify the ADC species most relevant to safety and efficacy. ADC bioanalysis need an integrated bioanalytical approach including ligand-binding assay (LBA) and LC-MS based assays to provide comprehensive characterization of the exposure/response relationship. This mini-review will summarize recent publications on ADC bioanalytical strategies and will focus on the publications within last three years on the advancement of hybrid ligand-binding/LC-MS methods for ADC PK and stability evaluation and for intact ADC-DAR distribution measurement to profile ADC biotransformation and catabolism. Special attention is paid to the publications on selection of ADC analytes, assay platforms and DAR characteristics of LBA as well as on the transition of the bioanalytical testing strategy at different phases of clinical development.

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“…There were comprehensive reviews on ADC bioanalytical assay future science group Research Article Wang, Gu, Liu et al strategies and challenges [10][11][12][13], and on in vivo biotransformation [14] and characterization of ADC catabolism [15]. An overview of analytes and ADC bioanalytical strategies was also outlined in a recent industry white paper on ADME characterization of ADCs from the 'ADC ADME working group' of the International Consortium for Innovation and Quality in Pharmaceutical Development [16] and in reviews of ADME properties of therapeutic proteins [17], and of characterization of ADCs by MS [18]. In depth coverage of LBA in ADC bioanalysis from early to late preclinical development was the subject of one recent review [19], while the validation of an integrated series of LBAs for clinical studies was described in another article [20].…”

mentioning

confidence: 98%