In Vivo Biotransformations of Antibody–Drug Conjugates

Abstract

The selective delivery of potent pharmacologically active compounds to target tissue or cells by antibody-drug conjugates makes this immuno-conjugate a promising modality for the treatment of cancers. A thorough understanding of the structural integrity of the linker, the payload and the conjugation site during biological exposure is critical throughout the process of novel linker-payload design and optimization of PK profile. This understanding is a key aspect of the effort to maximize efficacy while minimizing toxicity in preclinical testing and to ensure the translation to the clinical setting. The complexity of this bioconjugate modality is a source of significant challenge for analytical interrogation and analysis in vivo. Therefore, we report herein a survey of various types of biotransformation events that have been elucidated in recent years.

Molecular Basis of Valine-Citrulline-PABC Linker Instability in Site-Specific ADCs and Its Mitigation by Linker Design

“…Various degrees of instability in the systemic circulation have been observed for many ADCs bearing commonly utilized linkers, such as the decoupling of the maleimide-based linker payloads resulting in reduced ADC exposure, the premature loss of disulfide-linked payloads leading to shortened pharmacokinetic profiles, as well as the degradation of the payload moiety itself (7)(8)(9).…”

Bioanalysis of Antibody–Drug Conjugates

“…Challenges in ADC discovery from a perspective of drug design and analytical characterization are presented Rao et al [5]. In a related review manuscript various protocols applied for analysis of the in vivo biotransformation of ADCs are presented and substantiated by a survey of various types of biotransformation events reported in the literature [6]. Kumar et al present a stage relevant approach to LBA support for ADC bioanalysis specifically focusing on the impact of the DAR parameter on LBA-based measurement of various ADC analytes [7].…”

Antibody–Drug Conjugate Bioanalysis Using Lb-LC–MS/MS Hybrid Assays: Strategies, Methodology and Correlation to Ligand-Binding Assays

“…Similarly, the analyte in the 'antibody conjugated-payload' (assay 3 as commonly referred [10]) is antibody linked to at least one payload and unbound to the soluble target. In some ADC chemistry, the payload can be conjugated to other plasma proteins through linker exchange [14,[51][52][53]. Quantifying the payload conjugated to the drug antibody and all other plasma proteins could provide useful information for payload-dependent toxicity.…”

“…As a highlight, the AAPS Drug Conjugate Working Group issued a position paper on bioanalysis of ADCs in which definitions of ADC analytes and bioanalytical assays were discussed [9]. 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].…”