Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor

Kyriakos P. Papadopoulos, Randi Isaacs, Sanela Bilic, Kerstin Kentsch, Heather A. Huet, Matthias Hofmann, Drew Rasco, Nicole Kundamal, Zhongwhen Tang, Jennifer Cooksey, Amit Mahipal

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52 Scopus citations

Abstract

Purpose: TAS266 is a novel agonistic tetravalent Nanobody® targeting the DR5 receptor. In preclinical studies, TAS266 was more potent than a cross-linked DR5 antibody or TRAIL. This first-in-human study was designed to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of TAS266. Methods: Adult patients with advanced solid tumors were to receive assigned doses of TAS266 (3, 10, 15, or 20 mg/kg) intravenously on days 1, 8, 15, and 22 of a 28-day treatment cycle. Results: Grade ≥3 elevations in aspartate aminotransferase and/or alanine aminotransferase levels, occurring during cycle 1 in three of four patients at the 3 mg/kg dose level, were attributed to TAS266 and led to early study termination. Liver enzyme levels quickly returned to grade ≤1 following TAS266 discontinuation. Evidence of preexisting antibodies able to bind to TAS266 was found in the three patients who experienced these dose-limiting toxicities. Immunogenic responses remained elevated and strengthened at end-of-treatment (EOT). In the one patient who did not develop hepatotoxicity, no evidence of immunogenicity was observed at baseline or following administration of 4 TAS266 doses; however, incipient positive immunogenicity was observed at the EOT visit. Conclusion: TAS266 was associated with unexpected, significant but reversible hepatotoxicity. Although the underlying mechanism is not fully elucidated, factors including the molecule's high potency, immunogenicity to TAS266, and possibly increased DR5 expression on hepatocytes further enhancing the activity of the Nanobody® may have contributed to enhanced DR5 clustering and activation of hepatocyte apoptosis.

Original languageEnglish (US)
Pages (from-to)887-895
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume75
Issue number5
DOIs
StatePublished - May 1 2015
Externally publishedYes

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Keywords

  • DR5 receptor
  • Hepatotoxicity
  • Immunogenicity
  • Nanobody
  • TAS266

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Papadopoulos, K. P., Isaacs, R., Bilic, S., Kentsch, K., Huet, H. A., Hofmann, M., Rasco, D., Kundamal, N., Tang, Z., Cooksey, J., & Mahipal, A. (2015). Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor. Cancer Chemotherapy and Pharmacology, 75(5), 887-895. https://doi.org/10.1007/s00280-015-2712-0