%0 Journal Article
%T Quantitative pharmacology in antibody-drug conjugate development: armed antibodies or targeted small molecules?
%A Eshita Khera
%A Greg M. Thurber
%A Ian Nessler
%J Archive of "Oncoscience".
%D 2018
%R 10.18632/oncoscience.435
%X There is a major push in drug development to efficiently generate clinically effective antibody-drug conjugates (ADCs), fueled by two recent FDA approvals. ADCs consist of a large monoclonal antibody (¡«150 kDa) conjugated to potent, cytotoxic small molecule payloads through a chemical linker. These ¡®hybrid¡¯ drugs couple the properties of small molecule therapeutics with macromolecular biologics and function through multiple mechanisms of action (MoA). These include receptor-signaling modulation, cytotoxic payload delivery, and Fc-domain mediated functions such as antibody dependent cellular cytotoxicity (ADCC) and antigen presentation through dendritic cells (Figure (Figure1).1). The various components driving each of these mechanisms, including target and payload selection, antibody properties (isotype, affinity, alternative scaffolds), linker, and dosing (Drug-Antibody Ratio/DAR, schedule), can dramatically shape the development of new agents. However, the relative contribution of each MoA to overall efficacy is generally unknown, particularly in the clinic. This leads to differing perspectives: some view ADCs as ¡®targeted small molecules¡¯ driven by the efficacy of the payload, whereas others view them as ¡®armed antibodies¡¯ leveraging antibody MoA. While this may first appear to be a semantic argument, quantifying the contribution from each distinct MoA to overall efficacy for this drug class is an essential step towards rationally guiding their clinical development
%K antibody-drug conjugate
%K mechanism of action
%K immune cell recruitment
%K payload delivery
%K receptor signaling
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049322/