(1) Paquette M (2) Vilera-Perez LG (3) Beaudoin S (4) Ekindi-Ndongo N (5) Boudreaut PL (6) Bonin MA (7) Battista MC (8) Bentourkia M (9) Lopez AF (10) Lecomte R (11) Marsault E (12) Guerin B (13) Sabbagh R (14) Leyton JV

Oncoimmunology | Free PMC Article

Despite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor-specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor alpha-subunit (IL-5Ralpha) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Ralpha as a target for antibody-conjugates to better manage patients with MIBC. Patients were recruited and their tumors were processed for IL-5Ralpha immunohistochemical analysis. NOD/SCID mice were also heterotopically implanted with the human MIBC HT-1376 and HT-B9 cell lines and established xenografts immunohistochemically evaluated for IL-5Ralpha and compared against patient tumors. Using the mAb A14, an antibody-drug conjugate (ADC) and a radiolabeled immunoconjugate (RIC) were developed by conjugating to vinblastine and to the positron emitter copper-64 (64Cu), respectively. As a proof-of-concept for ADC and RIC efficacy, in vitro cytotoxicity and in vivo positron emission tomography (PET) imaging in tumor-bearing mice were performed, respectively. In addition, as rapid internalization and accumulation are important components for effective antibody-conjugates, we evaluated these aspects in response to IL-5 and 64Cu-A14 treatments. Our findings suggest that although IL-5Ralpha protein expression is preferentially increased in MIBC, it is rapid IL-5Ralpha-mediated internalization allowing vinblastine-A14 to have cytotoxic activity and 64Cu-A14 to detect MIBC tumors in vivo. This is the first report to elucidate the potential of IL-5Ralpha as an attractive MIBC target for antibody-conjugate applications.

Author Info: (1) Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences (FMHS), Centre hospitalier universitaire de Sherbrooke (CHUS), Universite de Sherbrooke

Author Info: (1) Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences (FMHS), Centre hospitalier universitaire de Sherbrooke (CHUS), Universite de Sherbrooke (UdeS), Sherbrooke, Quebec, Canada. (2) Department of Pathology, FMHS, CHUS, UdeS, Sherbrooke, Quebec, Canada. (3) Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences (FMHS), Centre hospitalier universitaire de Sherbrooke (CHUS), Universite de Sherbrooke (UdeS), Sherbrooke, Quebec, Canada. (4) Department of Pathology, FMHS, CHUS, UdeS, Sherbrooke, Quebec, Canada. (5) Department of Pharmacology and Physiology, FMHS, CHUS, UdeS, Sherbrooke, Quebec, Canada. (6) Peptide Chemistry Platform, UdeS, Sherbrooke, Quebec, Canada. (7) Division of Endocrinology, Department of Medicine and Department of Obstetrics and Gynecology, FMHS, CHUS, Sherbrooke, Quebec, Canada. (8) Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences (FMHS), Centre hospitalier universitaire de Sherbrooke (CHUS), Universite de Sherbrooke (UdeS), Sherbrooke, Quebec, Canada. Sherbrooke Molecular Imaging Centre (SMIC), Centre de recherche du CHUS (CRCHUS), Sherbrooke, Quebec, Canada. Sherbrooke Pharmacology Institute, Sherbrooke, Quebec, Canada. (9) The Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia. (10) Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences (FMHS), Centre hospitalier universitaire de Sherbrooke (CHUS), Universite de Sherbrooke (UdeS), Sherbrooke, Quebec, Canada. Sherbrooke Molecular Imaging Centre (SMIC), Centre de recherche du CHUS (CRCHUS), Sherbrooke, Quebec, Canada. Sherbrooke Pharmacology Institute, Sherbrooke, Quebec, Canada. (11) Department of Pharmacology and Physiology, FMHS, CHUS, UdeS, Sherbrooke, Quebec, Canada. Sherbrooke Pharmacology Institute, Sherbrooke, Quebec, Canada. (12) Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences (FMHS), Centre hospitalier universitaire de Sherbrooke (CHUS), Universite de Sherbrooke (UdeS), Sherbrooke, Quebec, Canada. Sherbrooke Molecular Imaging Centre (SMIC), Centre de recherche du CHUS (CRCHUS), Sherbrooke, Quebec, Canada. Sherbrooke Pharmacology Institute, Sherbrooke, Quebec, Canada. (13) Department of Surgery, FMHS, CHUS, UdeS, Sherbrooke, Quebec, Canada. (14) Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences (FMHS), Centre hospitalier universitaire de Sherbrooke (CHUS), Universite de Sherbrooke (UdeS), Sherbrooke, Quebec, Canada. Sherbrooke Molecular Imaging Centre (SMIC), Centre de recherche du CHUS (CRCHUS), Sherbrooke, Quebec, Canada. Sherbrooke Pharmacology Institute, Sherbrooke, Quebec, Canada.

Citation: Oncoimmunology 2017 6:e1331195 Epub05/19/2017

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/29123949

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