The anti-tumor efficacy of 3C23K, a glyco-engineered humanized anti-MISRII antibody, in an ovarian cancer model is mainly mediated by engagement of immune effector cells
| Autor: | Toufik Abache, Lucie Verhaeghe, Christine Gaucher, Thierry Chardès, André Pèlegrin, Aurélie Terrier, Alexandre Pichard, Isabelle Navarro-Teulon, Jean-Pierre Pouget, Alexandre Fontayne, Martine Pugnière, Pauline Estupina, Olivier Dubreuil, Marion Le Blay, Christophe De Romeuf, Alexis Rossignol, Jean-François Prost, Jean-Marc Barret, Maeva Chauvin, Emmanuel Deshayes, Nathalie Kersual, Marta Jarlier |
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| Přispěvatelé: | Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Institut du Cancer de Montpellier (ICM), Laboratoire Français du fractionnement et des Biotechnologies, GamaMabs Pharma SA [Toulouse] ( Centre Pierre Potier), Oncopole de Toulouse-Centre Pierre Potier [Toulouse], Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Clean Cells, Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO, Laboratoire Français du Fractionnement et des Biotechnologies (LFB), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Glycosylation medicine.medical_treatment Apoptosis Protein Engineering MISRII chemistry.chemical_compound 0302 clinical medicine Antibody-dependent cell-mediated cytotoxicity Ovarian Neoplasms biology 3. Good health ovarian cancer Oncology MESH: Antibodies Monoclonal Humanized/pharmacology Antineoplastic Agents/pharmacology Ovarian Neoplasms/drug therapy Receptors Peptide/immunology 030220 oncology & carcinogenesis therapeutic antibody Female immunotherapy Antibody Research Paper Receptors Peptide medicine.drug_class Cell Survival Mice Nude Antineoplastic Agents [SDV.CAN]Life Sciences [q-bio]/Cancer [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics Monoclonal antibody Antibodies Monoclonal Humanized Affinity maturation 03 medical and health sciences In vivo Cell Line Tumor medicine Animals Humans business.industry Antibody-Dependent Cell Cytotoxicity Immunotherapy [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy GCT medicine.disease Xenograft Model Antitumor Assays Carboplatin 030104 developmental biology chemistry Immunology biology.protein Cancer research Ovarian cancer business Receptors Transforming Growth Factor beta |
| Zdroj: | Oncotarget Oncotarget, Impact journals, 2017, 8 (23), pp.37061-37079. ⟨10.18632/oncotarget.15715⟩ Oncotarget, 2017, 8 (23), pp.37061-37079. ⟨10.18632/oncotarget.15715⟩ |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.15715⟩ |
| Popis: | International audience; Ovarian cancer is the leading cause of death in women with gynecological cancers and despite recent advances, new and more efficient therapies are crucially needed. Müllerian Inhibiting Substance type II Receptor (MISRII, also named AMHRII) is expressed in most ovarian cancer subtypes and is a novel potential target for ovarian cancer immunotherapy. We previously developed and tested 12G4, the first murine monoclonal antibody (MAb) against human MISRII. Here, we report the humanization, affinity maturation and glyco-engineering steps of 12G4 to generate the Fc-optimized 3C23K MAb, and the evaluation of its in vivo anti-tumor activity. The epitopes of 3C23K and 12G4 were strictly identical and 3C23K affinity for MISRII was enhanced by a factor of about 14 (KD = 5.5 × 10-11 M vs 7.9 × 10-10 M), while the use of the EMABling® platform allowed the production of a low-fucosylated 3C23K antibody with a 30-fold KD improvement of its affinity to FcγRIIIa. In COV434-MISRII tumor-bearing mice, 3C23K reduced tumor growth more efficiently than 12G4 and its combination with carboplatin was more efficient than each monotherapy with a mean tumor size of 500, 1100 and 100 mm3 at the end of treatment with 3C23K (10 mg/kg, Q3-4D12), carboplatin (60 mg/kg, Q7D4) and 3C23K+carboplatin, respectively. Conversely, 3C23K-FcKO, a 3C23K form without affinity for the FcγRIIIa receptor, did not display any anti-tumor effect in vivo. These results strongly suggested that 3C23K mechanisms of action are mainly Fc-related. In vitro, antibody-dependent cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) were induced by 3C23K, as demonstrated with human effector cells. Using human NK cells, 50% of the maximal lysis was obtained with a 46-fold lower concentration of low-fucosylated 3C23K (2.9 ng/ml) than of 3C23K expressed in CHO cells (133.35 ng/ml). As 3C23K induced strong ADCC with human PBMC but almost none with murine PBMC, antibody-dependent cell phagocytosis (ADCP) was then investigated. 3C23K-dependent (100 ng/ml) ADCP was more active with murine than human macrophages (only 10% of living target cells vs. about 25%). These in vitro results suggest that the reduced ADCC with murine effectors could be partially balanced by ADCP activity in in vivo experiments. Taken together, these preclinical data indicate that 3C23K is a new promising therapeutic candidate for ovarian cancer immunotherapy and justify its recent introduction in a phase I clinical trial. |
| Databáze: | OpenAIRE |
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