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Abstract
Rituximab (RTX), a chimeric IgG1 monoclonal antibody directed against the CD20 antigen, has revolutionized the treatment of B-cell malignancies. Nevertheless, the relapsed/refractory rates are still high. One strategy to increase the clinical effectiveness of RTX is based on antibody-cytokine fusion protein (immunocytokine; ICK) vectorizing together at the tumor site the antibody effector activities and the cytokine co-signal required for the generation of cytotoxic cellular immunity. Such ICKs linking various antibody formats to interleukin (IL)-2 are currently being investigated in clinical trials and have shown promising results in cancer therapies. IL-15, a structurally-related cytokine, is now considered as having a better potential than IL-2 in antitumor immunotherapeutic strategies. We have previously engineered the fusion protein RLI, linking a soluble form of human IL-15Rα-sushi+ domain to human IL-15. Compared with IL-15, RLI displayed better biological activities in vitro and higher antitumor effects in vivo in murine and human cancer models. In this study, we investigated the advantages of fusing RLI to RTX. Anti-CD20-RLI kept its binding capacity to CD20, CD16 and IL-15 receptor and therefore fully retained both antibody effector functions (ADCC and CDC), and the cytokine potential of RLI. In a severe combined immunodeficiency (SCID) mouse model of disseminated residual lymphoma, anti-CD20-RLI was found to induce long-term survival of 90% of mice up to at least 120 days whereas RLI and RTX, alone or in combination, just delayed the disease onset (100% of death at 28, 40 and 51 days respectively). These findings suggest that such ICK could improve the clinical efficacy of RTX, particularly in patients with refractory B-cell lymphoma.
Disclosure of Potential Conflicts of Interest
A.Q., D.B., and Y.J. are co-founders and shareholders of Cytune Pharma. The remaining authors declare no competing financial interests.
Acknowledgments
M.V. was supported by fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche and the Association pour la Recherche sur le Cancer. The authors thank Sébastien Morisseau for helpful advices and technical assistance, Karine Bernardeau and Klara Echasserieau (Recombinant Protein Facility) for site-exclusion chromatography analysis, and Virginie Maurier for in vivo technical assistance.
Financial support
INSERM, CNRS, Institut National du Cancer and Cancéropole Grand Ouest (MabImpact), OSEO Innovation and Région Pays de Loire (CIMATH2), Agence Nationale de la Recherche (Investissement d’avenir, LabEx MabImprove ANR-10-LABX53), Ministère de l’Enseignement Supérieur et de la Recherche, Association pour la Recherche sur le Cancer and Ligue contre le Cancer.