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Unexpected Hepatotoxicity in a Phase I Study of TAS266, a Novel Tetravalent Agonistic Monoclonal Nanobody® Targeting the DR5 Receptor

Papadopoulos, Kyriakos, Isaacs, Randi, Bilic, Sanela, Kentsch, Kerstin, Huet, Heather, Hofmann, Matthias, Rasco, Drew, Kundamal, Nicole, Tang, Zhongwen, Cooksey, Jennifer and Mahipal, Amit (2015) Unexpected Hepatotoxicity in a Phase I Study of TAS266, a Novel Tetravalent Agonistic Monoclonal Nanobody® Targeting the DR5 Receptor. Cancer, Chemotherapy, and Pharmacology.


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 (AST) and/or alanine aminotransferase (ALT) levels, occurring during cycle 1 in 3 of 4 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 pre-existing antibodies able to bind to TAS266 was found in the 3 patients who experienced these dose-limiting toxicities. Immunogenic responses remained elevated and strengthened at end-of-treatment (EOT). In the 1 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.

Item Type: Article
Keywords: Key words: hepatotoxicity, TAS266, Nanobody®, DR5 receptor, immunogenicity
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11