Abstract 647: CD20-specific Engineered Toxin Body demonstrates direct cell kill of multiple B-cell Non-Hodgkin's lymphoma types

Abstract

Abstract The B-cell membrane protein CD20 is expressed by both benign and neoplastic lymphocytes. It has been a superb target for immunotherapies targeting B-cell derived diseases. There are several anti-CD20 antibodies which have been developed for B-cell lymphoma therapy. The most successful example of this targeted approach is rituximab, which is approved for front and second line therapy of Non-Hodgkin lymphoma (NHL). However, rituximab has limited direct cell-kill effects, acting primarily through indirect immune responses induced by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC). While CD20-targeted radiotherapeutics have shown promise, their administrative challenges have curtailed their clinical utility. Thus, a therapeutic approach with direct cell-kill activity against CD20-expressing cells would be clinically useful. We have developed an engineered toxin body (ETB) comprising a CD20 scFv and a modified Shiga-like Toxin A (MT-3724) capable of specifically recognizing and killing CD20 expressing cells. MT-3724 is selectively cytotoxic against B-cell NHL cell lines and against NHL cells obtained from patients. It demonstrated potent cytotoxicity against Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma with IC (50) values ranging from 1.4 nM to 12 nM. Through immunofluorescent tracking, MT-3724 internalizes within one hour after binding to CD20 (+) B cells. To our knowledge, this is the first example of efficient internalization of an immunotoxin via CD20. Consistent with the in vitro activity, MT-3724 demonstrated anti-tumor efficacy in mice-bearing NHL cell line xenografts. These results show that MT-3724 is a promising targeted therapeutic agent against CD20 positive B-cell lymphomas and is currently under further development. Citation Format: Sangeetha Rajagopalan, Rachel Wirth, Jennifer Erdman, Kari Grant, Brigitte Brieschke, Rodney Flores, William Null, Jen-Sing Liu, Erin K. Willert, Jack P. Higgins. CD20-specific Engineered Toxin Body demonstrates direct cell kill of multiple B-cell Non-Hodgkin's lymphoma types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 647. doi:10.1158/1538-7445.AM2014-647