An anti-CD20–IL-2 immunocytokine is highly efficacious in a SCID mouse model of established human B lymphoma

• Published in: Blood 2005-05, Vol.105 (10), p.3972-3978
• Main Authors: Gillies, Stephen D., Lan, Yan, Williams, Steven, Carr, Frank, Forman, Stephen, Raubitschek, Andrew, Lo, Kin-Ming
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - immunology; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20 - immunology; Apoptosis; Cell Line, Tumor; Disease Models, Animal; Humans; Immunotherapy; Interleukin-2 - immunology; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - immunology; Mice; Mice, Inbred BALB C; Mice, SCID; Neoplasm Metastasis; Neoplasm, Residual - drug therapy; Neoplasm, Residual - immunology; Rituximab; Survival Rate; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-09-3533

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.