An, K

An, K. apoptosis, and cell-cycle modifications in AML cell lines and antitumor efficacy in orthotopic AML xenografts. Taken together, this study shows not only that AGS67E may serve as a potential therapeutic for B/T-cell malignancies, but it also demonstrates, for the first time, that CD37 is usually well expressed and a potential drug target in AML. == Introduction == The CD37 antigen is usually a transmembrane protein of the tetraspanin superfamily that is highly expressed on B cells during the pre-B to peripheral mature B-cell stages, but is usually absent on early B progenitor cells or terminally differentiated plasma cells (1,2). It is weakly expressed in a subset of peripheral blood mononuclear cells (PBMC) and in tissues where lymphocytes reside/infiltrate (1). Although the exact physiologic role of CD37 is usually unclear, it has been implicated as a signaling Mouse monoclonal to BLK death receptor (3), and observations from knockout mice suggest that it is not essential for B-cell development, but may function to regulate B/T-cell interactions/proliferation as well as aspects of humoral and cellular immune responses (4,5). With respect to cancer, CD37 is highly expressed on malignant B cells in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL; ref.6). Consequently, CD37 represents a encouraging therapeutic target for B-cell malignancies. Anti-CD20 antibodies, such as rituximab, of a tumumab, and obinutuzamab, have proven to be effective for the treatment of NHL and CLL, either as single brokers or in combination therapy (7,8). The intrinsic anticancer activities of these antibodies include direct signaling/proapoptotic activity, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity. However, many patients eventually relapse or experience resistance to available treatments, creating a need for additional therapeutic options. The clinical experience with CD37 targeted brokers is still in its infancy and is as follows: (i) radioimmunotherapy with131I-MB-1 in patients with NHL who experienced relapse resulted in some limited clinical responses, but this agent was not further developed as a therapeutic drug (9,10); (ii) a CD37-binding small modular immunopharmaceutical protein (TRU-016) with apoptosis and ADCC-inducing abilities has advanced into clinical testing as a treatment for B-cell malignancies (11); (iii) an Fc-engineered antibody to CD37 (BI836826), also with ADCC and apoptosis-inducing functionality, is in early development (12); (iv) IMGN-529, an antibodydrug conjugate that combines the intrinsic proapoptotic and immune effector activities of its anti-CD37 antibody component with the cytotoxic potency of its DM1 BI-4916 maytansinoid payload, is also in development (13). Encouraged by the clinical successes of ADCETRIS (brentuximab vedotin; ref.14) and KADCYLA (ado-trastuzumab emtansine; ref.15), the currently approved ADCs targeting malignancy, we have developed AGS67E, a fully human anti-CD37 IgG2 antibody conjugated to the potent microtubule-disrupting agent monomethyl auristatin E (MMAE) via reduced cysteines and the protease-cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl. Unlike all other reported therapeutic CD37 antibodies, including the recently reported IMGN-529 ADC (13), the unconjugated antibody component of BI-4916 our ADC does not exhibit intrinsic apoptotic or ADCC activity. The activity of AGS67E derives from its MMAE payload, which is usually selectively delivered by a highly specific antibody (AGS67C). Once delivered, AGS67E induces apoptosis, cell-cycle alterations, and cytotoxicityin vitroas well as antitumor efficacyin vivo. Because the preclinical potency of our agent is similar or superior to the reported preclinical efficacy of other CD37 antibodies in comparable models of B-cell malignancies (1113), we postulated that adding ADCC and apoptosis-inducing capabilities to our unconjugated antibody was unnecessary, and further that it could prove to be a liability from a toxicology or pharmacokinetic perspective. Aside from a novel CD37 ADC that we statement here, we also report, for the first time, that CD37 is usually well expressed in T-cell lymphomas and AML and that AGS67E exhibits potent antitumor efficacy in preclinical models of AML, including patient-derived models. Moreover, we show that CD37 is usually differentially expressed in BI-4916 CD34+CD38AML versus normal stem cells. Taken together, our findings suggest that AGS67E may serve as a potential therapeutic for B/T-cell malignancies as well as AML. To our knowledge, this body of work is the first demonstrating that CD37 is usually well expressed and a potential drug target in.