Unexpected thrombocytopenia and anemia in cynomolgus monkeys induced by a therapeutic human monoclonal antibody

Nancy Everds, Nianyu Li, Keith Bailey, Madeline Fort, Riki Stevenson, Remi Jawando, Kevin Salyers, Vibha Jawa, Padma Narayanan, Erin Stevens, Ching He, Mai Phuong Nguyen, Sam Tran, Nancy Doyle, Florence Poitout-Belissent, Jacquelin Jolette, Cen Xu, Katherine Sprugel

Research output: Contribution to journalArticlepeer-review

Abstract

Cynomolgus monkeys dosed with a therapeutic monoclonal antibody (mAbY.1) at ≥50 mg/kg had unexpected acute thrombocytopenia (nadir ∼3,000 platelets/μl), sometimes with decreases in red cell mass. Increased activated macrophages, mitotic figures, and erythrophagocytosis were observed in the spleen. Binding of mAbY.1 to cynomolgus peripheral blood cells could not be detected in vitro. mAbY.1 induced phagocytosis of platelets by peripheral blood monocytes from cynomolgus monkeys, but not from humans. mAbs sharing the same constant domain (Fc) sequences, but differing from mAbY.1 in their variable domains, bound competitively to and had similar biological activity against the intended target. None of these antibodies had hematologic liabilities in vitro or in vivo. Neither the F(ab')2 portion of mAbY.1 nor the F(ab')2 portion on an aglycosylated Fc (IgG1) framework caused phagocytosis of platelets in vitro. These data suggest that the hematologic effects of mAbY.1 in cynomolgus monkeys likely occurred through an off-target mechanism, shown to be driven by 1 to 3 amino acid differences in the light chain. The hematologic effects made mAbY.1 an unsuitable candidate for further development as a therapeutic agent. This example demonstrates that nonclinical safety studies may be essential for understanding off-target effects of mAbs prior to clinical trials.

Original languageEnglish (US)
Pages (from-to)951-969
Number of pages19
JournalToxicologic Pathology
Volume41
Issue number7
DOIs
StatePublished - Oct 1 2013
Externally publishedYes

Keywords

  • cynomolgus monkey
  • hemophagocytosis
  • macrophage activation
  • monoclonal antibody
  • off-target effects
  • phagocytosis
  • thrombocytopenia

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Toxicology
  • Cell Biology

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