학술논문
Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5)
Research Articles
Research Articles
Document Type
Report
Author
Source
Cancer Biotherapy & Radiopharmaceuticals. February 2010, Vol. 25 Issue 1, p13, 7 p.
Subject
Language
English
ISSN
1084-9785
Abstract
Introduction The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, is a type 2 membrane protein that is expressed in the majority of [...]
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. Key words: antibody, apoptosis, cancer, immunotherapy, targeted therapy
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. Key words: antibody, apoptosis, cancer, immunotherapy, targeted therapy