Phase I study of YS110, a recombinant humanized monoclonal antibody to CD26, in Japanese patients with advanced malignant pleural mesothelioma

Abstract

Objectives: CD26 is a transmembrane glycoprotein with dipeptidyl peptidase IV activity that is overexpressed in malignant pleural mesothelioma (MPM). We performed a phase I study to determine the maximum tolerated dose, pharmacokinetics, and antitumor activity of YS110, a monoclonal antibody to CD26, in Japanese patients with MPM intolerant of or refractory to prior standard therapies. Material and methods: The study was designed as an open-label, 3 + 3 dose-escalation, phase I trial. Patients were sequentially assigned to three dosing cohorts (2, 4, or 6 mg/kg). Each 6-week treatment cycle consisted of YS110 administration weekly for 5 weeks followed by a 1-week rest period. Treatment was continued until disease progression, death, or intolerable toxicity. Corticosteroid, antihistamine, and acetaminophen administration before each infusion was adopted to limit infusion-related reactions (IRRs). Results: Nine Japanese patients (seven men and two women, mean age of 62.2 years), three in each dosing cohort, were enrolled in the study. No patient developed a dose-limiting toxicity. Adverse events of grade 3 or 4 developed in seven patients, with the most common such event being a decreased lymphocyte count. Two patients had mild or moderate IRRs. The serum concentration of YS110 increased in a dose-dependent manner. Among seven patients evaluable for tumor response, four showed stable disease and one achieved a partial response. Conclusions: YS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study.

Tumor‐associated macrophage‐derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma

“…The expression levels of the transcripts of these CSC markers were similarly increased by rhIL‐1β stimulation (Figure 2B). Among these CSC markers, we focused on CD26, which has been recently reported to be clinically actionable by a novel monoclonal antibody, YS‐110 27 . Consistent with the results for the transcripts, flow cytometry analysis demonstrated that cell surface CD26 expression was upregulated in a time‐dependent manner by rhIL‐1β stimulation (Figure 2C).…”

“…Among these CSC markers, we focused on CD26, which has been recently reported to be clinically actionable by a novel monoclonal antibody, YS-110. 27 Consistent with the results for the transcripts, flow cytometry analysis demonstrated that cell surface CD26 expression was upregulated in a time-dependent manner by rhIL-1β stimulation (Figure 2C). We further investigated the pathway involved in rhIL-1β-induced CD26 upregulation.…”

“…YS‐110 was reported to exert antitumor effect against MPM cells through inducing antibody‐dependent cell‐mediated cytotoxicity and cell cycle arrest via p27 kip1 accumulation 39 . According to the results of phase I clinical trial, YS‐110 therapy was well tolerable and showed durable effect for some patients with MPM 27,40 . A phase II study to evaluate antitumor effect for the treatment of MPM is now ongoing.…”

“…39 According to the results of phase I clinical trial, YS-110 therapy was well tolerable and showed durable effect for some patients with MPM. 27,40 A phase II study to evaluate antitumor effect for the treatment of MPM is now ongoing. Canakinumab was originally approved for the treatment of patients with chronic inflammatory disease including cryopyrin-associated periodic syndrome, juvenile idiopathic arthritis, and refractory gout.…”

CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions

“…In terms of tumor response, four of seven patients had stable disease, while one achieved a partial response. This phase I trial showed that YS110 administration yielded promising antineoplastic outcome in advanced MPM while remaining relatively well-tolerated, similar to the FIH trial reported previously [26].…”