First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers

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Abstract

Background:

YS110 is a humanised IgG1 monoclonal antibody with high affinity to the CD26 antigen. YS110 demonstrated preclinical anti-tumour effects without significant side effects.

Methods:

This FIH study was designed to determine the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) to assess the tolerance, pharmacokinetics (PK) and pharmacodynamics profiles of YS110 and preliminary efficacy. YS110 were initially administered intravenously once every 2 weeks (Q2W) for three doses and then, based on PK data, once every week (Q1W) for five doses in patients with CD26-expressing solid tumours.

Results:

Thirty-three patients (22 mesothelioma) received a median of 3 (range 1–30) YS110 infusions across six dose levels (0.1–6 mg kg ^-1). MTD was not reached and two dose-limiting toxicities (infusion hypersensitivity reactions) led to the institution of a systemic premedication. Low-grade asthenia (30.3%), hypersensitivity (27.3%), nausea (15.2%), flushing (15.2%), chills (12.1%) and pyrexia (12.1%) were reported as ADRs. Pharmacokinetic parameters (AUC and C _max) increased in proportion with the dose. sCD26/DPPIV assays indicated CD26 modulation. Prolonged stable diseases were observed in 13 out of 26 evaluable patients.

Conclusions:

YS110 is well tolerated up to 6 mg kg ^-1 Q1W, which has been defined as the RP2D, with encouraging prolonged disease stabilisations observed in a number of patients with advanced/refractory mesothelioma.

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Most cited references 36

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A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer.

Roberta WC Pang, Wai Law, Andrew Chu … (2010)

Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer metastasis is unclear. Here, we identified a subpopulation of CD26(+) cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26(+) cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26(+) cells, but not CD26(-) cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26(+) cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy. Copyright 2010 Elsevier Inc. All rights reserved.

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Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy.

Rosa Barreira da Silva, Melissa E Laird, Nader Yatim … (2015)

The success of antitumor immune responses depends on the infiltration of solid tumors by effector T cells, a process guided by chemokines. Here we show that in vivo post-translational processing of chemokines by dipeptidylpeptidase 4 (DPP4, also known as CD26) limits lymphocyte migration to sites of inflammation and tumors. Inhibition of DPP4 enzymatic activity enhanced tumor rejection by preserving biologically active CXCL10 and increasing trafficking into the tumor by lymphocytes expressing the counter-receptor CXCR3. Furthermore, DPP4 inhibition improved adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade. These findings provide direct in vivo evidence for control of lymphocyte trafficking via CXCL10 cleavage and support the use of DPP4 inhibitors for stabilizing biologically active forms of chemokines as a strategy to enhance tumor immunotherapy.

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Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada.

Jan P Van Meerbeeck, Rabab Gaafar, Christian Manegold … (2005)

We conducted a phase III trial to determine whether first-line treatment with raltitrexed, a thymidine synthase inhibitor, and cisplatin results in superior outcome compared with cisplatin alone in patients with malignant pleural mesothelioma (MPM). Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B). In patients with measurable disease, response was monitored using the Response Evaluation Criteria in Solid Tumors criteria. Health related quality of life (HRQOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Lung Module (QLQ-LC13). Two hundred fifty patients were randomized: 80% male; median age, 58 years; and WHO PS, 0, 1, 2 in 25, 62, and 13% of cases, respectively. There were no toxic deaths. The main grade 3 or 4 toxicities observed were neutropenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, response rate was 13.6% (arm A) versus 23.6% (arm B; P = .056). No difference in HRQOL was observed on any of the scales. Median overall and 1-year survival in arms A and B were 8.8 (95% CI, 7.8 to 10.8) v 11.4 months (95% CI, 10.1 to 15), respectively, and 40% v 46%, respectively (P = .048). A combination of raltitrexed and cisplatin improves overall survival compared with cisplatin alone. This study confirms that a combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM, without harmful effect on HRQOL.

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Author and article information

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Print): 25 April 2017

Publication date (Electronic): 14 March 2017

Publication date PMC-release: 25 April 2017

Volume: 116

Issue: 9

Pages: 1126-1134

Affiliations

[1 ]Gustave Roussy, Université Paris-Saclay, Drug Development Department (DITEP) , Villejuif, France

[2 ]Centre Georges-François Leclerc, Unité de Phases Précoces , Dijon, France

[3 ]Institut de Cancérologie des Hospices Civils de Lyon, CITOHL , Lyon, France

[4 ]Hôpital Cochin , Paris, France

[5 ]Centre Hospitalier Universitaire (CHU) de Caen, Centre de Recherche Clinique/Essais de phases précoces , Caen, France

[6 ]Gustave Roussy, Translational Research Laboratory , Villejuif, France

[7 ]FV Clinical subcontractor for SynteractHCR SAS , Levallois-Perret, France

[8 ]Y's therapeutics Inc. , Redwood City, CA, USA

[9 ]Kissei Pharmaceutical Co., Ltd , Tokyo, Japan

[10 ]Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo , Tokyo, Japan

[11 ]Division of Hematology/Oncology, University of Florida , Gainesville, FL, USA

[12 ]Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University , Tokyo, Japan

[13 ]Keio University School of Medicine , Tokyo, Japan

[14 ]Saitama Medical University , Saitama, Japan

[15 ]Y's AC Co., Ltd , Tokyo, Japan

Author notes

[* ]E-mail: eric.angevin@ 123456gustaveroussy.fr

Article

Publisher Item ID: bjc201762

DOI: 10.1038/bjc.2017.62

PMC ID: 5418443

PubMed ID: 28291776

SO-VID: 44427be8-44f7-4d6e-b04e-22568d1f448d

License:

This work is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

History

Date received : 08 November 2016

Date revision received : 17 February 2017

Date accepted : 20 February 2017

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First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers

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Abstract

Background:

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Results:

Conclusions:

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Karger: Oncology

Most cited references 36

A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer.

Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy.

Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada.

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Cited by 29

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