title: An anti-CD20-IL-2 immunocytokine is highly efficacious in a SCID mouse model of established human B lymphoma.
abstract: We have engineered an anti-CD20-interleukin 2 (IL-2) immunocytokine (ICK) based on the Leu16 anti-CD20 antibody and have deimmunized both the variable (V) regions as well as the junction between the heavy (H) chain constant region and IL-2. Mutations were made to remove potential T-cell epitopes identified by in silico binding to major histocompatibility complex (MHC) class II molecules. The resulting immunocytokine, DI-Leu16-IL-2, retained full anti-CD20 activity as assessed by fluorescence-activated cell-sorting (FACS) analysis, and had enhanced antibody-dependent cellular cytotoxicity (ADCC) effector function relative to the DI-Leu16 antibody or control anti-CD20 antibody (rituximab). In a severe combined immunodeficient (SCID) mouse model of disseminated, residual lymphoma, anti-CD20-IL-2 immunocytokines based on Leu16 were far more effective at a dose of 0.25 mg/kg than anti-CD20 antibody given at 25/mg/kg, despite a shorter half-life of the ICK. Anti-CD20-IL-2 was also far more effective than a control ICK targeted to an antigen with greatly reduced expression on Daudi tumor cells, or various combinations of anti-CD20 antibodies and IL-2. Antitumor activity of DI-Leu16-IL-2 was shown to partially but not entirely depend on Fc receptor (R) binding, suggesting that ADCC and targeting of IL-2 both play roles in the mechanism of tumor clearance. Based on these animal models, DI-Leu16-IL-2 could offer therapeutic potential for patients with CD20 positive lymphoma. Clinical trials are currently under development.
authors.affiliation: EMD Lexigen Research Center, Bedford Campus, 45A Middlesex Tpk, Billerica, MA 01821-3936, USA. sgillies@emdlexigen.com
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.forename: Yan
authors.initials: Y
authors.lastname: Lan
authors.forename: Steven
authors.initials: S
authors.lastname: Williams
authors.forename: Frank
authors.initials: F
authors.lastname: Carr
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Andrew
authors.initials: A
authors.lastname: Raubitschek
authors.forename: Kin-Ming
authors.initials: KM
authors.lastname: Lo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000276:immunology; D000069283:Rituximab; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D007376:Interleukin-2; D000069283:Rituximab