Pharmacokinetic comparison of a diverse panel of non-targeting human antibodies as matched IgG1 and IgG2 isotypes in rodents and non-human primates

Kenneth W Walker; Hossein Salimi-Moosavi; Gregory E Arnold; Qing Chen; Marcus Soto; Frederick W Jacobsen; John Hui

doi:10.1371/journal.pone.0217061

Pharmacokinetic comparison of a diverse panel of non-targeting human antibodies as matched IgG1 and IgG2 isotypes in rodents and non-human primates

PLoS One. 2019 May 23;14(5):e0217061. doi: 10.1371/journal.pone.0217061. eCollection 2019.

Authors

Kenneth W Walker¹, Hossein Salimi-Moosavi¹, Gregory E Arnold¹, Qing Chen¹, Marcus Soto¹, Frederick W Jacobsen¹, John Hui¹

Affiliation

¹ Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, United States of America.

Abstract

In this study we compared the pharmacokinetic profile of four unrelated antibodies, which do not bind to mammalian antigens, in IgG1 and IgG2 frameworks in both rats and non-human primates (NHP). This allowed for extensive cross comparison of the impact of antibody isotype, complementarity determining regions (CDR) and model species on pharmacokinetics without the confounding influence of antigen binding in the hosts. While antibody isotype had no significant impact on the pharmacokinetics, the CDRs do alter the profile, and there is an inverse correlation between the neonatal Fc receptor (FcRn) affinity and pharmacokinetic performance. Faster clearance rates were also associated with higher isoelectric points; however, although this panel of antibodies all possess basic isoelectric points, ranging from 8.44 to 9.18, they also have exceptional in vivo half-lives, averaging 369 hours, and low clearance rates, averaging 0.18 ml/h/kg in NHPs. This pattern of pharmacokinetic characteristics was conserved between rats and NHPs.

Publication types

Comparative Study

MeSH terms

Animals
Antibodies / metabolism*
Antibodies, Monoclonal / immunology
CHO Cells
Complementarity Determining Regions / immunology
Cricetinae
Cricetulus
Histocompatibility Antigens Class I / immunology
Humans
Immunoglobulin G / metabolism*
Male
Mice
Pharmacokinetics
Primates / immunology
Protein Binding
Rats
Rats, Sprague-Dawley
Receptors, Fc / immunology

Substances

Antibodies
Antibodies, Monoclonal
Complementarity Determining Regions
Histocompatibility Antigens Class I
Immunoglobulin G
Receptors, Fc
Fc receptor, neonatal

Grants and funding

Amgen provided support in the form of salaries for all authors as well as materials and facilities to conduct the studies, but Amgen did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript with the exception that senior Amgen management as well as the legal depart did review and approve the manuscript for publication. The specific roles of these authors are articulated in the ‘author contributions’ section.