The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies.
The application of protein engineering technologies toward successfully improving antibody pharmacokinetics has been challenging due to the multiplicity of biochemical factors that influence monoclonal antibody (mAb) disposition in vivo. Physiological factors including interactions with the neonatal Fc receptor (FcRn) and specific antigen binding properties of mAbs, along with biophysical properties of the mAbs themselves play a critical role. It has become evident that applying an integrated approach to understand the relative contribution of these factors is critical to rationally guide and apply engineering strategies to optimize mAb pharmacokinetics. The study presented here evaluated the influence of unintended non-specific interactions on the disposition of mAbs whose clearance rates are governed predominantly by either non-specific (FcRn) or target-mediated processes. The pharmacokinetics of 8 mAbs representing a diverse range of these properties was evaluated in cynomolgus monkeys. Results revealed complementarity-determining region (CDR) charge patch engineering to decrease charge-related non-specific binding can have a significant impact on improving the clearance. In contrast, the influence of enhanced in vitro FcRn binding was mixed, and related to both the strength of charge interaction and the general mechanism predominant in governing the clearance of the particular mAb. Overall, improved pharmacokinetics through enhanced FcRn interactions were apparent for a CDR charge-patch normalized mAb which was affected by non-specific clearance. The findings in this report are an important demonstration that mAb pharmacokinetics requires optimization on a case-by-case basis to improve the design of molecules with increased therapeutic application.
a Departments of Drug Disposition and Development/Commercialization, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center , Indianapolis , IN , USA.
Amita
A
Datta-Mannan
b Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center , Indianapolis , IN , USA.
Jirong
J
Lu
b Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center , Indianapolis , IN , USA.
Derrick R
DR
Witcher
c Biotechnology Discovery Research, Applied Molecular Evolution, Eli Lilly and Company ; San Diego , CA , USA.
Donmienne
D
Leung
c Biotechnology Discovery Research, Applied Molecular Evolution, Eli Lilly and Company ; San Diego , CA , USA.
Ying
Y
Tang
a Departments of Drug Disposition and Development/Commercialization, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center , Indianapolis , IN , USA.
Victor J
VJ
Wroblewski
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D000915:Antibody Affinity / Q000276:immunology; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D051379:Mice; D011485:Protein Binding / Q000276:immunology; D015202:Protein Engineering / Q000379:methods*; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism*
D061067:Antibodies, Monoclonal, Humanized; D022801:Complementarity Determining Regions; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal
antibody pharmacokinetics; charge interactions of IgGs; neonatal Fc receptor (FcRn); non-specific binding; target mediated disposition