TRU-016 is a SMIPTM (monospecific protein therapeutic) molecule against the tetraspanin transmembrane family protein CD37 that is currently in Phase 2 tests in Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). of SMIP-016GV as low at 5E?6 μg/mL on cells expressing minimal CD37 antigen. In support of the biological relevance of this SMIP-016GV mediates effective ADCC against main acute lymphoblastic leukemia (ALL) cells with low surface expression of CD37. Collectively these data suggest potential use of the novel restorative agent SMIP-016GV with enhanced effector function for B cell malignancies including CLL and ALL therapy. Keywords: CD37 CLL ALL NVP-AEW541 Protein Therapeutics Introduction CD37 is definitely a tetraspanin transmembrane family protein that is expressed on the surface of adult immunoglobulin-producing B cells1 but not in CD10+ CD34+ and CD34- B cell precursors found in the bone marrow. Surface CD37 expression becomes strong in CD10- adult B-lymphocytes and its expression further raises as the B-lymphocytes continue to mature and move into the lymph nodes and peripheral blood. Finally surface CD37 manifestation is definitely lost in terminally differentiated plasma B cells.2 3 CD37 is also highly expressed on the surface of transformed mature B cell leukemia and lymphoma cells but not on myeloma cells.3 CD37 is dimly expressed on T cells monocytes and granulocytes and is not expressed on the surface of natural killer (NK) cells platelet NVP-AEW541 and erythrocytes.1 2 This limited expression makes it an ideal therapeutic target in B cell malignancies2 such as chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). CD37 was first examined like a potential restorative target in the late 1980s. Radio-labeled mouse monoclonal antibodies against CD37 were analyzed in B cell lymphoma individuals and were shown to create anti-tumor reactions.4-6 However due to the perceived targeting potential of CD20 CD37 like a therapeutic target was not further developed until recently with an engineered monoclonal antibody mAb 37.1 that has been shown to be effective in preclinical models of B cell malignancies.7 Furthermore our laboratory has shown that a novel protein therapeutic directed against CD37 SMIP-016 induces more apoptosis in CLL B cells than rituximab8 in vitro when it is Rabbit polyclonal to IL1R2. used alongside an anti-human Fc crosslinking antibody. Its mechanism of action is definitely through a caspase self-employed pathway which suggests it can be used in combination therapy with additional caspase activation-dependent cytotoxic antibody therapies or chemotherapeutic providers such as fludarabine. The direct cytotoxic effect of SMIP-016 on CLL B cells is definitely proportional to the amount of CD37 present within the cell surface making it a highly selective therapy toward malignant B cells. Furthermore SMIP-016 showed potent anti-lymphoma activity inside a Raji/SCID xenograft mouse model. TRU-016 a humanized anti-CD37 SMIP molecule derived from SMIP-016 is currently in Phase 2 clinical tests and showing solitary agent activity in CLL.9 In addition to direct killing a major potential mechanism involved in TRU-016 tumor elimination is ADCC. SMIP-016 induced NK cells mediated antibody-dependent cellular cytotoxicity (ADCC) both in vitro and in vivo.8 Monoclonal antibodies with bisected complex non-fucosylated oligosaccharides attached to the asparagine 297 residue in the CH2 region bind with increased affinity to FcγRIIIa.10 This glycoform engineering has been shown to enhance ADCC11 through cells bearing FcγRIIIa an important component in how monoclonal antibodies are clinically effective.12 For example afucosylated anti-CD20 antibodies display higher B cell depletion than their fucosylated counterpart by reaching saturated ADCC levels at lower concentrations and through improved FcγRIIIa binding.13 In addition it has been reported that antibodies NVP-AEW541 lacking the core fucose in Fc oligosaccharides elicit high ADCC reactions by two mechanisms.14 Within the effector cell part afucosylated anti-CD20 antibodies were less inhibited by human being plasma IgG. On the prospective cells cells treated with non-fucosylated anti-CD20 antibodies showed markedly stronger binding to NK NVP-AEW541 cells than fucosylated anti-CD20.14 Due to the success of the parent compound SMIP-016 we sought to determine if NVP-AEW541 modifying the Fc oligosaccharides of a SMIP protein would enhance its activity. Herein we describe a second generation anti-CD37 SMIP molecule SMIP-016GV with an afucosylated Fc receptor binding region designed for enhanced effector function. Our data demonstrates SMIP-016GV has enhanced effector function with NK cells and monocyte derived macrophages (MDM) making it an.