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Death receptor 5 agonistic antibody PRO95780: preclinical pharmacokinetics and concentration–effect relationship support clinical dose and regimen selection

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Abstract

Purpose

PRO95780, a human monoclonal antibody (mAb) against death receptor 5 (DR5/TRAIL-R2/TNFRSF10B), was developed for the treatment for cancer. Our objective was to characterize pharmacokinetics (PK) in mice, rats, and cynomolgus monkeys and concentration–effect relationships of PRO95780 in xenograft mouse models of human cancers; this would guide the selection of dose and regimen for clinical trials.

Methods

The PK profiles were determined in mice, rats, and cynomolgus monkeys. Three xenograft models with a wide range of in vitro sensitivities to PRO95780 were selected for efficacy studies. Tumoristatic serum concentrations (TSCs) were determined using PK/pharmacodynamic (PD) modeling with tumor growth as a PD endpoint. A species-invariant time PK scaling method was employed to estimate disposition in humans using PK data in cynomolgus monkeys. Furthermore, the predicted human PK parameters were used to estimate dose and regimen to achieve TSC observed in mice at the steady-state trough concentrations (C trough ss) in the clinic.

Results

Linear PK was observed across species. A serum concentration of 22 μg/mL was identified to be the target TSC in mice. A dose of 10 mg/kg administered once every 2 weeks (Q2W) was predicted to achieve a TSC at C trough ss in 95 % of patients.

Conclusions

PRO95780 has linear PK in mice, rats, and monkeys. Estimated TSCs varied among different xenograft models. A projected target dose in humans is achievable for Q2W administration within the dose range used for other commercial mAbs.

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Acknowledgments

We thank Shannon Stainton, Mike Reich, Amy Oldendorp, and Michelle Gonzales from in vivo studies group in the Safety Assessment Department at Genentech Inc. for performing efficacy and PK studies and the BioAnalytical Assays Department at Genentech Inc. for providing PK assay data. The authors wish to thank Drs. Frank P. Theil, Saileta Prabhu, and Leslie A. Khawli and others from Genentech Inc. for reviewing the manuscript. The authors thank PRO95780 project team members for their valuable discussion.

Conflict of interest

Authors are employees at Genentech/Roche and hold stock in Roche.

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Authors and Affiliations

  1. Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Hong Xiang, Arthur E. Reyes II & Steve Eppler

  2. Portfolio Management and Operations, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Sean Kelley & Lisa A. Damico-Beyer

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  1. Hong Xiang
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  2. Arthur E. Reyes II
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Correspondence to Hong Xiang.

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Xiang, H., Reyes, A.E., Eppler, S. et al. Death receptor 5 agonistic antibody PRO95780: preclinical pharmacokinetics and concentration–effect relationship support clinical dose and regimen selection. Cancer Chemother Pharmacol 72, 405–415 (2013). https://doi.org/10.1007/s00280-013-2200-3

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  • DOI: https://doi.org/10.1007/s00280-013-2200-3

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