Clinical pharmacology strategies in supporting drug development and approval of antibody–drug conjugates in oncology

Abstract

Antibody–drug conjugates (ADCs) are important molecular entities in the treatment of cancer. These conjugates combine the target specificity of monoclonal antibodies with the potent anti-cancer activity of small-molecule therapeutics. The complex structure of ADCs poses unique challenges to characterize the drug’s pharmacokinetics (PKs) and pharmacodynamics (PDs) since it requires a quantitative understanding of the PK and PD properties of multiple different molecular species (e.g., ADC conjugate, total antibody and unconjugated cytotoxic drug). As a result, clinical pharmacology strategy of an ADC is rather unique and dependent on the linker/cytotoxic drug technology, heterogeneity of the ADC, PK and safety/efficacy profile of the specific ADC in clinical development. In this review, we summarize the clinical pharmacology strategies in supporting development and approval of ADCs using the approved ADCs as specific examples to illustrate the customized approach to clinical pharmacology assessments in their clinical development.

Covariate analysis of tusamitamab ravtansine, a DM4 anti‐CEACAM5 antibody‐drug conjugate, based on first‐in‐human study

“…16 , 17 For other approved ADCs, payload PKs are reported either in separate models, or in integrated models where ADC and cytotoxic concentrations are described together. 18 The present analysis is the first semimechanistic model (including DAR measurement) which evaluate covariates impact on SAR408701 ADC and its derivatives simultaneously.…”

“…Exponential impact of such weight‐related covariates is included in all PK models of published ADCs. 18 Allometric exponents can be fixed to their theoretical values 19 : 1 for volumes and 0.75 for clearances (e.g., gemtuzumab ozogamicin 20 ), but they usually are estimated (e.g., inotuzumab ozogamicin, 21 trastuzumab emtansine, 22 and polatuzumab vedotin 23 ). On Li et al 24 integrated two‐analytes PK model, BW effect was fixed on metabolite PK parameters but estimated on ADC parameters.…”

Quantification for Antibody-Conjugated Drug in Trastuzumab Emtansine and Application to In Vitro Linker Stability and In Vivo Pharmacokinetic Study in Rat Using an Immuno-Affinity Capture Liquid Chromatography-Mass Spectrometric Method

“…Recently, more attention is paid to the importance of the in vivo acDrug levels of ADCs regarding the efficacy, in vivo drug-antibody ratio (DAR) evaluation, and toxicity. Currently, only ADCs with cleavable linkers are easily applicable to the quantitation of acDrug by the immuno-affinity capture method followed by on-bead digestion using specific enzymes such as cathepsin B or beta-glucuronidase for the LC-MS analysis of acDrug [16][17][18]. Due to lack of specific sites in the linker, this method was not applicable to Kadcyla, which contains non-cleavable linkers.…”

The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment

“…Antibody-drug conjugates are structurally complex, consisting of multiple conjugated and unconjugated molecular species, and, as such, pose unique challenges for characterization of their pharmacokinetics (PK) and pharmacodynamics (PDs). 3 Monoclonal antibody affinity for the antigen is crucial for the success of targeted therapies such as ADCs. To achieve high treatment efficacy, mAbs must have favorable PK and PD profiles.…”

“…Antibody-drug conjugate constructs are one example of the “magic bullet” concept proposed more than 100 years ago by Paul Ehrlich, 2 where a specific cellular target could be exploited to selectively treat diseases. Antibody-drug conjugates are structurally complex, consisting of multiple conjugated and unconjugated molecular species, and, as such, pose unique challenges for characterization of their pharmacokinetics (PK) and pharmacodynamics (PDs) 3 …”