title: Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: South Texas Accelerated Research Therapeutics, 4383 Medical Drive, Suite 4021, San Antonio, TX, 78229, USA, kyri.papadopoulos@start.stoh.com.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Randi
authors.initials: R
authors.lastname: Isaacs
authors.forename: Sanela
authors.initials: S
authors.lastname: Bilic
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kentsch
authors.forename: Heather A
authors.initials: HA
authors.lastname: Huet
authors.forename: Matthias
authors.initials: M
authors.lastname: Hofmann
authors.forename: Drew
authors.initials: D
authors.lastname: Rasco
authors.forename: Nicole
authors.initials: N
authors.lastname: Kundamal
authors.forename: Zhongwhen
authors.initials: Z
authors.lastname: Tang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cooksey
authors.forename: Amit
authors.initials: A
authors.lastname: Mahipal
mesh_terms: D000368:Aged; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D061905:Single-Domain Antibodies / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000276:immunology
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D061905:Single-Domain Antibodies