CD81: a novel lymphoma therapeutic target

Abstract Tetraspanin CD81 was initially described as a target of a monoclonal antibody (mAb) able to inhibit proliferation of lymphomas and activated lymphocytes, which suggests that CD81 plays a role in their survival. Indeed, studies in CD81 knockout mice have demonstrated its role in innate and adaptive immune responses, by regulating lymphocyte activation, proliferation and antibody production. Furthermore, CD81 deficiency leads to reduced anti-tumor immune suppression by MDSCs and Tregs, resulting in decreased tumor growth and metastasis. Moreover, treatment with anti-mouse CD81 mAbs reduces metastasis in tumor-bearing wild type mice. Here we demonstrate that an anti-human CD81 mAb effectively reduces growth of lymphoma cell lines in vivo and improves survival. To further enhance the in vivo efficacy of our mouse IgG1 anti-CD81 mAb, we class switched the hybridoma to produce IgG2a and we also engineered a chimeric human IgG1 anti-CD81 mAb. Indeed, both isotypes when compared to Rituximab, show superior efficacy in eliminating tumor cells in vivo. And in vitro studies demonstrate superior direct killing, antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Finally, despite the expression of CD81 on normal lymphocytes which creates a challenge for antibody-based therapies, we demonstrate that B cell lymphoma cell lines were selectively sensitive to anti-CD81 therapy. Taken together, we proposed CD81 as a potential target for treating lymphoma.