title: Mechanistic Projection of First-in-Human Dose for Bispecific Immunomodulatory P-Cadherin LP-DART: An Integrated PK/PD Modeling Approach.
abstract: A bispecific immunomodulatory biotherapeutic molecule (P-cadherin LP-DART) based on the Dual Affinity Re-Targeting (DART) scaffold has been developed as a potential antitumor treatment showing efficacy in preclinical testing. A minimal anticipated biological effect level (MABEL) approach was applied to project the first-in-human (FIH) dose, because of its immune agonistic properties following target engagement. The pharmacological activity of P-cadherin LP-DART is driven by binding to both P-cadherin on the tumor cells and CD3 on T cells. Therefore, the concentration of the tri-molecular synapse formed between drug, T cell, and tumor cell, rather than drug concentration, is responsible for efficacy. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD)-driven approach was explored to understand the exposure-response relationship based on the synapse concentration to project the MABEL dose. Orthogonal approaches including PK-driven and receptor occupancy calculations were also investigated. This study showcases the application of PK/PD modeling in immune-oncology, and could potentially be implemented for other bispecific biotherapeutics.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut, USA.|Current Address: Clinical Pharmacology and Pharmacometrics, Quantitative Sciences, Janssen Pharmaceuticals, Spring House, Pennsylvania, USA.
authors.forename: N
authors.initials: N
authors.lastname: Haddish-Berhane
authors.affiliation: MacroGenics, Rockville, Maryland, USA.
authors.forename: P
authors.initials: P
authors.lastname: Moore
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut, USA.
authors.forename: T
authors.initials: T
authors.lastname: Clark
authors.affiliation: MacroGenics, Rockville, Maryland, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: MacroGenics, Rockville, Maryland, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Clinical Pharmacology, Pfizer, San Diego, California, USA.
authors.forename: D
authors.initials: D
authors.lastname: Xuan
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Barton
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Betts
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer, Pearl River, New York, USA.
authors.forename: F
authors.initials: F
authors.lastname: Barletta
mesh_terms: D000818:Animals; D001682:Biological Availability; D015820:Cadherins / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D003601:Cytotoxicity Tests, Immunologic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D015820:Cadherins; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell