title: Translational pharmacokinetics and pharmacodynamics of an FcRn-variant anti-CD4 monoclonal antibody from preclinical model to phase I study.
abstract: MTRX1011A is a humanized anti-CD4 antibody with an amino acid substitution (N434H) to improve its binding to the neonatal Fc receptor (FcRn). Pharmacokinetic/pharmacodynamic (PK/PD) data in baboons suggest that the increased binding to FcRn reduces the nonspecific elimination rate (K(el)) of MTRX1011A by ~50% but does not affect its PK-PD relationship. The human PK/PD data of MTRX1011A from a phase I study in patients with rheumatoid arthritis (RA) were compared with those previously reported for TRX1, its predecessor antibody, using population PK-PD modeling. The results suggest a comparable PK-PD relationship and no significant difference between the K(el) values of the two antibodies. However, the results may have been confounded by the differences in the clinical populations in which the two antibodies were studied and the presence of preexisting immunoglobulin M (IgM) antibodies in the RA sera that recognize N434H in MTRX1011A. This study highlights the challenges in translating from animal studies to human application the effects of FcRn-directed mutations on the PK of monoclonal antibodies.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.forename: H
authors.initials: H
authors.lastname: Scheerens
authors.forename: J C
authors.initials: JC
authors.lastname: Davis
authors.forename: R
authors.initials: R
authors.lastname: Deng
authors.forename: S K
authors.initials: SK
authors.lastname: Fischer
authors.forename: C
authors.initials: C
authors.lastname: Woods
authors.forename: P J
authors.initials: PJ
authors.lastname: Fielder
authors.forename: E G
authors.initials: EG
authors.lastname: Stefanich
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D015704:CD4 Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D010215:Papio; D011961:Receptors, Fc / Q000378:metabolism*; D057170:Translational Research, Biomedical
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; C100688:Fc receptor, neonatal