Novel in Vivo and in Vitro Pharmacokinetic/Pharmacodynamic-Based Human Starting Dose Selection for Glofitamab.

Journal: Journal of pharmaceutical sciences
PMID: 34953862

Abstract

We present a novel approach for first-in-human (FIH) dose selection of the CD20xCD3 bispecific antibody, glofitamab, based on pharmacokinetic/pharmacodynamic (PKPD) assessment in cynomolgus monkeys to select a high, safe starting dose, with cytokine release (CR) as the PD endpoint. Glofitamab pharmacokinetics were studied in mice and cynomolgus monkeys; PKPD of IL-6, TNF-α and interferon-γ release following glofitamab, with/without obinutuzumab pretreatment (Gpt) was studied in cynomolgus monkeys. Potency differences for CR between cynomolgus monkeys and humans were determined by glofitamab incubation in whole blood of both species. The PKPD model for CR was translated to humans to project a starting dose that did not induce CR exceeding a clinically-predefined threshold. In cynomolgus monkeys, glofitamab showed a species-specific atypical high clearance, with and without B-cell debulking by Gpt. CR was related to glofitamab serum levels and B-cell counts. B-cell reduction by Gpt led to a marked decrease in CR. FIH starting dose (5 µg) was selected based on IL-6 release considering the markedly higher glofitamab in vitro potency in human vs monkey blood. This is a novel PKPD-based approach for selection of FIH starting dose for a CD20xCD3 bispecific antibody in B-cell lymphoma, evidenced in the glofitamab study, NP30179 (NCT03075696).

Authors

  • Nicolas Frances
    Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
  • Marina Bacac
    Roche Innovation Center Zürich, Roche Pharmaceutical Research and Early Development, Zürich, Switzerland.
  • Katharine Bray-French
    Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
  • François Christen
    Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
  • Heather Hinton
    Roche Innovation Center Zürich, Roche Pharmaceutical Research and Early Development, Zürich, Switzerland.
  • Elisabeth Husar
    Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
  • Elizabeth Quackenbush
    Roche Innovation Center New York, Roche Pharmaceutical Research and Early Development, New York City, NY.
  • Martin Schäfer
    Roche Innovation Center Munich, Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
  • Eginhard Schick
    Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
  • Arthur Van De Vyver
    Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Basel, Switzerland.
  • Wolfgang F Richter
    Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, Basel, Switzerland. Electronic address: wolfgang.richter@roche.com.

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