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Pharmacokinetic Properties of Humanized IgG1 and IgG4 Antibodies in Preclinical Species: Translational Evaluation

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ABSTRACT

Assessment of the factors that regulate antibody exposure–response relationships in the relevant animal models is critical for the design of successful translational strategies from discovery to the clinic. Depending on the specific clinical indication, preclinical development paradigms may require that the efficacy or dosing-related attributes for the existing antibody be assessed in various species when cross-reactivity of the lead antibody to the intended species is justified. Additionally, with the success of monoclonal antibodies for management of various human conditions, a parallel interest in therapeutic use of these novel modalities in various veterinary species has followed. The protective role of neonatal Fc receptor (FcRn) in regulation of IgG homeostasis and clearance is now well recognized and the “nonspecific clearance” of antibodies through bone marrow-derived phagocytic and vascular endothelial cells (via lysosomal processes) is modulated by interactions with FcRn receptors. In this study, we have attempted to examine the PK properties of human IgG antibodies in dog and monkey. These studies establish a translational framework for evaluation of IgG antibody PK properties across species.

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Notes

  1. Analogous human IgGs were described based upon Fc gamma, FcRn and complement binding: Human IgG1, 2, 3, and 4 are comparable to canine IgG B, A, C, and D, respectively (from reference (16)).

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Acknowledgments

The authors acknowledge Dr. Jason Goetzmann; Ms. Jane Fontenot (University of Louisiana at Lafayette) and Mr. Walter Knapp (Merck & Co., Inc., West Point, PA, USA) for their support of and contributions to this work.

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Authors and Affiliations

  1. Merck & Co., Inc, Palo Alto, California, USA

    Mohammad Tabrizi, Divas Neupane, Sophia E. Elie, Harish Shankaran, Shuli Zhang, SuChun Hseih, Laurence Fayadat-Dilman, Yaoli Song, Vaishnavi Ganti, Michael Judo, Wolfgang Seghezzi & Enrique Escandon

  2. Merck & Co., Inc, Boston, MA, USA

    Daping Zhang

  3. Merck & Co., Inc, West Point, PA, USA

    Daniel Spellman

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  1. Mohammad Tabrizi
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Correspondence to Mohammad Tabrizi.

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Tabrizi, M., Neupane, D., Elie, S.E. et al. Pharmacokinetic Properties of Humanized IgG1 and IgG4 Antibodies in Preclinical Species: Translational Evaluation. AAPS J 21, 39 (2019). https://doi.org/10.1208/s12248-019-0304-3

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