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Drug metabolism and disposition: the biological fate of chemicals
07, 2022;50 (7): 898-908.

Target-Mediated Drug Disposition Affects the Pharmacokinetics of Interleukin-10 Fragment Crystallizable Fusion Proteins at Pharmacologically Active Doses.

Zheng Yang, Surendran Rajendran, Vanessa Spires, Brian Poirson, Murali Gururajan, Zheng Lin, Jaren Arbanas, Stanley Krystek, James Loy, Yuan Cheng, Stephen Carl, Samantha Pace, Yun Wang, John Mehl, Shihua Xu, Krishna Vasudevan, Miranda Broz, Lois Lehman-McKeeman, Paul Morin, Robert F Graziano
Author Information
  1. Zheng Yang: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.) yangz@bms.com.
  2. Surendran Rajendran: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  3. Vanessa Spires: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  4. Brian Poirson: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  5. Murali Gururajan: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  6. Zheng Lin: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  7. Jaren Arbanas: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  8. Stanley Krystek: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  9. James Loy: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  10. Yuan Cheng: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  11. Stephen Carl: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  12. Samantha Pace: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  13. Yun Wang: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  14. John Mehl: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  15. Shihua Xu: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  16. Krishna Vasudevan: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  17. Miranda Broz: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  18. Lois Lehman-McKeeman: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  19. Paul Morin: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
  20. Robert F Graziano: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y.), Nonclinical Disposition and Bioanalysis (S.R., S.X.), Discovery Biotherapeutics (Z.L., J.A., P.M.), Molecular Structure and Design (S.K.), Discovery Pharmaceutics and Analytical Sciences, Pharmaceutical Candidate Optimization (Y.C., S.C., S.P., Y.W., J.M.), Discovery Oncology (V.S., B.P., M.G., R.F.G.), Translational Medicine (K.V.), and Pharmaceutical Candidate Optimization (L.L.-M.), Bristol Myers Squibb, Princeton, New Jersey; Discovery Toxicology, Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Cambridge, Massachusetts (J.L.); and Discovery Oncology, Bristol Myers Squibb, Redwood City, California (M.B.).
PMID: 35545256 DOI: 10.1124/dmd.121.000799

Abstract

Fragment crystallizable (Fc) fusion is commonly used for extending the half-life of biotherapeutics such as cytokines. In this work, we studied the pharmacokinetics of Fc-fused interleukin-10 (IL-10) proteins that exhibited potent antitumor activity in mouse syngeneic tumor models. At pharmacologically active doses of ���0.1 mg/kg, both mouse Fc-mouse IL-10 and human Fc-human IL-10, constructed as the C terminus of the Fc domain fused with IL-10 via a glycine-serine polypeptide linker, exhibited nonlinear pharmacokinetics after intravenous administration to mice at the doses of 0.05, 0.5, and 5 mg/kg. With a nominal dose ratio of 1:10:100; the ratio of the area under the curve for mouse Fc-mouse IL-10 and human Fc-human IL-10 was 1:181:1830 and 1:75:633, respectively. In contrast, recombinant mouse or human IL-10 proteins exhibited linear pharmacokinetics in mice. Compartmental analysis, using the Michaelis-Menten equation with the in���vitro IL-10 receptor alpha binding affinity inputted as the K, unified the pharmacokinetic data across the dose range. Additionally, nontarget-mediated clearance estimated for fusion proteins was ���200-fold slower than that for cytokines, causing the manifestation of target-mediated drug disposition (TMDD) in the fusion protein pharmacokinetics. The experimental data generated with a mouse IL-10 receptor alpha-blocking antibody and a human Fc-human IL-10 mutant with a reduced receptor binding affinity showed significant improvements in pharmacokinetics, supporting TMDD as the cause of nonlinearity. Target expression and its effect on pharmacokinetics must be determined when considering using Fc as a half-life extension strategy, and pharmacokinetic evaluations need to be performed at a range of doses covering pharmacological activity. SIGNIFICANCE STATEMENT: Target-mediated drug disposition can manifest to affect the pharmacokinetics of a fragment crystallizable (Fc)-fused cytokine when the nontarget-mediated clearance of the cytokine is decreased due to neonatal Fc receptor-mediated recycling and molecular weight increases that reduce the renal clearance. The phenomenon was demonstrated with interleukin-10 Fc-fusion proteins in mice at pharmacologically active doses. Future drug designs using Fc as a half-life extension approach for cytokines need to consider target expression and its effect on pharmacokinetics at relevant doses.

MeSH Term

Animals
Half-Life
Humans
Interleukin-10
Mice
Receptors, Interleukin-10
Recombinant Fusion Proteins

Chemicals

Receptors, Interleukin-10
Recombinant Fusion Proteins
Interleukin-10
Journal Article
Article has an altmetric score of 1

Word Cloud

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