Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein

Zheng Yang; James Loy; Brian Poirson; Yanshan Dai; Surendran Rajendran; Shihua Xu; Vanessa Spires; Murali Gururajan; Zheng Lin; Jaren Arbanas; Stephen Carl; Samantha Pace; Yun Wang; John Mehl; Krishna Vasudevan; Thomas Spires; Ruslan Novosiadly; Shodeinde Coker; Raymond Perez; Kelly Covello; Paul Morin; Robert Graziano; Miranda Broz; Lois Lehman-McKeeman

doi:10.3389/fphar.2022.829063

Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein

Front Pharmacol. 2022 Jun 20:13:829063. doi: 10.3389/fphar.2022.829063. eCollection 2022.

Authors

Zheng Yang¹, James Loy², Brian Poirson³, Yanshan Dai⁴, Surendran Rajendran⁴, Shihua Xu⁴, Vanessa Spires³, Murali Gururajan³, Zheng Lin⁵, Jaren Arbanas⁵, Stephen Carl⁶, Samantha Pace⁶, Yun Wang⁶, John Mehl⁶, Krishna Vasudevan⁷, Thomas Spires⁷, Ruslan Novosiadly⁷, Shodeinde Coker⁸, Raymond Perez⁸, Kelly Covello⁸, Paul Morin⁵, Robert Graziano³, Miranda Broz⁹, Lois Lehman-McKeeman¹⁰

Affiliations

¹ Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, NJ, United States.
² Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, MA, United States.
³ Discovery Oncology, Bristol Myers Squibb, Princeton, NJ, United States.
⁴ Nonclinical Disposition and Bioanalysis, Bristol Myers Squibb, Princeton, NJ, United States.
⁵ Discovery Biotherapeutics, Bristol Myers Squibb, Princeton, NJ, United States.
⁶ Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, NJ, United States.
⁷ Translational Medicine, Bristol Myers Squibb, Princeton, NJ, United States.
⁸ Oncology Early Clinical Development, Bristol Myers Squibb, Princeton, NJ, United States.
⁹ Discovery Oncology, Bristol Myers Squibb, Redwood City, CA, United States.
¹⁰ Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, NJ, United States.

Abstract

Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) was studied in mice for antitumor efficacy, and the elevation of interleukin-18 (IL-18) was examined as a PD biomarker. The in vivo mFc-mIL-10 EC₅₀ for the IL-18 induction was estimated to be 2.4 nM, similar to the in vitro receptor binding affinity (K_d) of 3.2 nM. The IL-18 induction was further evaluated in cynomolgus monkeys, where the in vivo induction EC₅₀ by a human IL-10 human Fc-fusion protein (hFc-hIL-10) was 0.08 nM vs. 0.3 nM measured as the in vitro K_d. The extent of the IL-18 induction correlated with mouse antitumor efficacy and was used to connect mouse efficacy to that in monkeys. The PD-based efficacious dose projected in monkeys was comparable to the results obtained using a PK-based method in which mouse efficacious exposure was targeted and corrected for affinity differences between the species. Furthermore, PK/PD relationships were developed for anemia and thrombocytopenia in monkeys treated with hFc-hIL-10, with thrombocytopenia predicted to be dose-limiting toxicity. Using quantitative pharmacology and toxicology information obtained through modeling work in the same species, the TI of hFc-hIL-10 in monkeys was determined to be 2.4 (vs. PD-based efficacy) and 1.2-3 (vs. PK-based efficacy), indicating a narrow safety margin. The model-based approaches were proven valuable to the developability assessment of the IL-10 Fc-fusion protein.

Keywords: Fc-fusion protein; IL-10; IL-18; anemia (therapy); pharmacodynamic biomarker; pharmacokinetic/pharmacodynamic modeling; therapeutic index; thrombocytopenia (therapy).

Copyright © 2022 Yang, Loy, Poirson, Dai, Rajendran, Xu, Spires, Gururajan, Lin, Arbanas, Carl, Pace, Wang, Mehl, Vasudevan, Spires, Novosiadly, Coker, Perez, Covello, Morin, Graziano, Broz and Lehman-McKeeman.