title: Pharmacokinetics of anti-IL17A and anti-IL22 peptide-antibody bispecific genetic fusions in mice.
abstract: The peptide-antibody (Ab) genetic fusion is a promising technology for targeting multiple antigens in a single Ab-like molecule. We have recently described generation and in vitro characterization of several such genetic fusions, using an interleukin (IL)-17A binding peptide and an anti-IL-22 Ab as a model system. In this study we assessed pharmacokinetic profiles of these model genetic fusions in mice. Specifically an IL-17A binding peptide was fused to either the heavy chain or both the heavy and the light chains of an anti-IL22 human IgG1 (referred to Compounds 1 or 2, respectively). Swiss Webster mice were given a single 10 mg/kg IV dose of Compound 1 or Compound 2 and serum concentrations were measured by a fused molecule immunoassay, in which IL-17A was used as a capture and anti-human IgG was used as a detector. In addition, serum samples were assayed using a total human IgG immunoassay. PK parameters were calculated by non-compartmental modeling. The two genetic fusions had similar PK profiles, with total body clearance of ~0.9-1.0 mL/h/kg, volume of distribution at steady-state of ~63-65 mL/kg, and elimination half-life of ~40 h. Our study provides the first characterization of the PK properties of peptide-Ab genetic fusions and suggests that although these genetic fusions appear to be eliminated faster than a typical Ab, the PK profile may be suitable for preclinical and clinical testing.
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, MA, United States; Clinical Pharmacology, Alexion Pharmaceutical, Inc., Cambridge, MA, United States. Electronic address: vugmeyster@hotmail.com.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vugmeyster
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, MA, United States.
authors.forename: Yiqun Etran
authors.initials: YE
authors.lastname: Zhang
authors.affiliation: Global Biotherapeutic Technologies, Pfizer Inc., Cambridge, MA, United States.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Development Management, Pfizer Inc., Cambridge, MA, United States.
authors.forename: Jill
authors.initials: J
authors.lastname: Wright
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, MA, United States.
authors.forename: Sheldon S
authors.initials: SS
authors.lastname: Leung
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D010455:Peptides / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000493:pharmacokinetics*; D000097043:Interleukin-22
chemical_list: D018033:Antibodies, Bispecific; D007074:Immunoglobulin G; D020381:Interleukin-17; D007378:Interleukins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D000097043:Interleukin-22
keywords: Antibody; Bi-functional pharmacokinetics; Bi-specific; Genetic fusion; Peptide