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

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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.

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Acknowledgments

The authors thank Syntaxx Communications, Inc who provided manuscript development and medical writing services, with the support of Novartis Pharmaceuticals Corporation and to Glenda Chambers, the TAS266 study coordinator at South Texas Accelerated Research Therapeutics.

Conflict of interest

SB and ZT are employees of Novartis Pharmaceuticals Corporation. RI, NK, HH, KK, SB, and MH are employees of Novartis Institutes for Biomedical Research. RI, NK, HH, and ZT own stock in Novartis Pharmaceuticals Corporation. START received funding from Novartis Pharmaceuticals Corporation for conduct of this clinical trial by KP and DR. JC and AM have no conflict of interest.

Author information

Authors and Affiliations

  1. South Texas Accelerated Research Therapeutics, 4383 Medical Drive, Suite 4021, San Antonio, TX, 78229, USA

    Kyriakos P. Papadopoulos & Drew Rasco

  2. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    Randi Isaacs, Sanela Bilic, Nicole Kundamal & Zhongwhen Tang

  3. DMPK/DMPK-Biologics, Novartis Institutes for Biomedical Research, Basel, Switzerland

    Kerstin Kentsch & Matthias Hofmann

  4. Novartis Institutes for Biomedical Research, Cambridge, MA, USA

    Heather A. Huet

  5. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Jennifer Cooksey & Amit Mahipal

Authors
  1. Kyriakos P. Papadopoulos
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  2. Randi Isaacs
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  3. Sanela Bilic
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  4. Kerstin Kentsch
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  8. Nicole Kundamal
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  9. Zhongwhen Tang
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Correspondence to Kyriakos P. Papadopoulos.

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Papadopoulos, K.P., Isaacs, R., Bilic, S. et al. Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor. Cancer Chemother Pharmacol 75, 887–895 (2015). https://doi.org/10.1007/s00280-015-2712-0

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  • DOI: https://doi.org/10.1007/s00280-015-2712-0

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