Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5)

Andres Forero-Torres, Jatin Shah, Tina Wood, James Posey, Ronda Carlisle, Catherine Copigneaux, F. Luo, Slawomir Wojtowicz-Praga, Ivor Percent, Mansoor Saleh

Research output: Contribution to journalArticlepeer-review

125 Citations (Scopus)

Abstract

Background: TRA-8 is a murine agonist monoclonal antibody to death receptor 5 (DR5), which is able to trigger apoptosis in DR5 positive human tumor cells without the aid of crosslinking. It has demonstrated cytotoxicity in vitro and in vivo antitumor efficacy to a wide range of solid tumors in murine xenograft models. Tigatuzumab is a humanized IgG1 monoclonal antibody derived from TRA-8. Methods: A phase I trial of tigatuzumab in patients with relapsed/refractory carcinomas (n=16) or lymphoma (n=1) was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety. Three to six (3-6) patients were enrolled in successive escalating cohorts at doses ranging from 1 to 8mg/kg weekly. Results: Seventeen (17) patients enrolled, 9 in the 1-, 2-, and 4-mg/kg dose cohorts (3 in each cohort) and 8 in the 8-mg/kg dose cohort. Tigatuzumab was well tolerated with no DLTs observed, and the MTD was not reached. There were no study-drug-related grade 3 or 4, renal, hepatic, or hematologic toxicities. Plasma half-life was 6-10 days, and no anti-tigatuzumab responses were detected. Seven (7) patients had stable disease, with the duration of response ranging from 81 to 798 days. Conclusions: Tigatuzumab is well tolerated, and the MTD was not reached. The high number of patients with stable disease suggests antitumor activity.

Original languageEnglish
Pages (from-to)13-19
Number of pages7
JournalCancer Biotherapy and Radiopharmaceuticals
Volume25
Issue number1
DOIs
Publication statusPublished - 1 Feb 2010
Externally publishedYes

Keywords

  • Antibody
  • Apoptosis
  • Cancer
  • Immunotherapytargeted therapy

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