Considerations for the nonclinical safety evaluation of antibody drug conjugates for oncology

Abstract

Antibody drug conjugates (ADCs) include monoclonal antibodies that are linked to cytotoxic small molecules. A number of these agents are currently being developed as anti-cancer agents designed to improve the therapeutic index of the cytotoxin (i.e., cytotoxic small molecule or cytotoxic agent) by specifically delivering it to tumor cells. This paper presents primary considerations for the nonclinical safety evaluation of ADCs and includes strategies for the evaluation of the entire ADC or the various individual components (i.e., antibody, linker or the cytotoxin). Considerations are presented on how to design a nonclinical safety assessment program to identify the on- and off-target toxicities to enable first-in-human (FIH) studies. Specific discussions are also included that provide details as to the need and how to conduct the studies for evaluating ADCs in genetic toxicology, tissue cross-reactivity, safety pharmacology, carcinogenicity, developmental and reproductive toxicology, biotransformation, toxicokinetic monitoring, bioanalytical assays, immunogenicity testing, test article stability and the selection of the FIH dose. Given the complexity of these molecules and our evolving understanding of their properties, there is no single all-encompassing nonclinical strategy. Instead, each ADC should be evaluated on a case-by-case scientifically-based approach that is consistent with ICH and animal research guidelines.

Keywords: ADC; ADME; Antibody drug conjugates; Biotherapeutics; Cytotoxin; EFD; ELISA; FIH; GLP; Good Laboratory Practice; HNSTD; ICH; International Conference on Harmonisation; LBA; LC/MS/MS; Linker; MS; MTD; PD; PK; Payload; Regulatory toxicology; STD(10); Safety assessment; TCR; TK; V(d); absorption, distribution, metabolism and elimination; antibody-drug conjugate; embryofetal development; enzyme-linked immunosorbent assay; first-in-human; hERG; highest non-severely toxic dose in non-rodent species; human ether-à-go-go related gene; ligand binding assay; liquid chromatography–tandem mass spectrometry; mass spectrometry; maximum tolerated dose; pharmacodynamics; pharmacokinetics; severely toxic dose in 10% of rodents; tissue cross-reactivity; toxicokinetics; volume of distribution.