title: Optimal Affinity of a Monoclonal Antibody: Guiding Principles Using Mechanistic Modeling.
abstract: Affinity optimization of monoclonal antibodies (mAbs) is essential for developing drug candidates with the highest likelihood of clinical success; however, a quantitative approach for setting affinity requirements is often lacking. In this study, we computationally analyzed the in vivo mAb-target binding kinetics to delineate general principles for defining optimal equilibrium dissociation constant ([Formula: see text]) of mAbs against soluble and membrane-bound targets. Our analysis shows that in general [Formula: see text] to achieve 90% coverage for a soluble target is one tenth of its baseline concentration ([Formula: see text]), and is independent of the dosing interval, target turnover rate or the presence of competing ligands. For membrane-bound internalizing targets, it is equal to the ratio of internalization rate of mAb-target complex and association rate constant ([Formula: see text]). In cases where soluble and membrane-bound forms of the target co-exist, [Formula: see text] lies within a range determined by the internalization rate ([Formula: see text]) of the mAb-membrane target complex and the ratio of baseline concentrations of soluble and membrane-bound forms ([Formula: see text]). Finally, to demonstrate practical application of these general rules, we collected target expression and turnover data to project [Formula: see text] for a number of marketed mAbs against soluble (TNFα, RANKL, and VEGF) and membrane-bound targets (CD20, EGFR, and HER2).
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck, West Point, Pennsylvania, USA.
authors.forename: Anson K
authors.initials: AK
authors.lastname: Abraham
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen, South San Francisco, California, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Harrold
authors.affiliation: EMD Serono, Billerica, Massachusetts, USA.
authors.forename: Anup
authors.initials: A
authors.lastname: Zutshi
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts, USA. pratap.singh.charan@gmail.com.
authors.forename: Pratap
authors.initials: P
authors.lastname: Singh
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D008024:Ligands; D008565:Membrane Proteins; D011506:Proteins
keywords: PK half-life; binding affinity; lead optimization; membrane-bound target; soluble target