First in human dose calculation of a single-chain bispecific antibody targeting glioma using the MABEL approach.

Journal Article (Journal Article)

BACKGROUND: First-in-human (FIH) clinical trials require careful selection of a safe yet biologically relevant starting dose. Typically, such starting doses are selected based on toxicity studies in a pharmacologically relevant animal model. However, with the advent of target-specific and highly active immunotherapeutics, both the Food and Drug Administration and the European Medicines Agency have provided guidance that recommend determining a safe starting dose based on a minimum anticipated biological effect level (MABEL) approach. METHODS: We recently developed a T cell activating bispecific antibody that effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma in mice (hEGFRvIII:CD3 bi-scFv). hEGFRvIII:CD3 bi-scFv is comprized of two single chain antibody fragments (bi-scFvs) that bind mutant epidermal growth factor receptor variant III (EGFRvIII), a mutation frequently seen in malignant glioma, and human CD3ε on T cells, respectively. In order to establish a FIH dose, we used a MABEL approach to select a safe starting dose for hEGFRvIII:CD3 bi-scFv, based on a combination of in vitro data, in vivo animal studies, and theoretical human receptor occupancy modeling. RESULTS: Using the most conservative approach to the MABEL assessment, a dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/kg body weight was selected as a safe starting dose for a FIH clinical study. CONCLUSIONS: The comparison of our MABEL-based starting dose to our in vivo efficacious dose and the theoretical human receptor occupancy strongly supports that our human starting dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/patient kg will be safe.

Full Text

Duke Authors

Cited Authors

  • Schaller, TH; Snyder, DJ; Spasojevic, I; Gedeon, PC; Sanchez-Perez, L; Sampson, JH

Published Date

  • April 2020

Published In

Volume / Issue

  • 8 / 1

PubMed ID

  • 32273346

Pubmed Central ID

  • 32273346

Electronic International Standard Serial Number (EISSN)

  • 2051-1426

Digital Object Identifier (DOI)

  • 10.1136/jitc-2019-000213

Language

  • eng

Conference Location

  • England