title: Highly potent anti-CD20-RLI immunocytokine targeting established human B lymphoma in SCID mouse.
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.
authors: Marie
authors: M
authors: Vincent
authors: Géraldine
authors: G
authors: Teppaz
authors: Laurie
authors: L
authors: Lajoie
authors: Véronique
authors: V
authors: Solé
authors: Anne
authors: A
authors: Bessard
authors: Mike
authors: M
authors: Maillasson
authors: Séverine
authors: S
authors: Loisel
authors: David
authors: D
authors: Béchard
authors: Béatrice
authors: B
authors: Clémenceau
authors: Gilles
authors: G
authors: Thibault
authors: Laure
authors: L
authors: Garrigue-Antar
authors: Yannick
authors: Y
authors: Jacques
authors: Agnès
authors: A
authors: Quéméner
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C568159:IL-15Ralpha-sushi domain-linker-IL-15 fusion protein; C508594:IL2 protein, human; D018796:Immunoconjugates; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D000069283:Rituximab