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 Blood, 15 May 2005, Vol. 105, No. 10, pp. 3972-3978.
Prepublished online as a Blood First Edition Paper on February 3, 2005; DOI 10.1182/blood-2004-09-3533.

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IMMUNOBIOLOGY

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

Stephen D. Gillies, Yan Lan, Steven Williams, Frank Carr, Stephen Forman, Andrew Raubitschek, and Kin-Ming Lo

From the EMD Lexigen Research Center, Billerica, MA; Biovation, Aberdeen, Scotland; and Department of Radioimmunotherapy, City of Hope National Medical Center, Duarte, CA.

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.


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