AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody–Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML

Abstract

CD37 is a tetraspanin expressed on malignant B cells. Recently, CD37 has gained interest as a therapeutic target. We developed AGS67E, an antibody–drug conjugate that targets CD37 for the potential treatment of B/T-cell malignancies. It is a fully human monoclonal IgG2 antibody (AGS67C) conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent mono-methyl auristatin E (MMAE). AGS67E induces potent cytotoxicity, apoptosis, and cell-cycle alterations in many non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) cell lines and patient-derived samples in vitro. It also shows potent antitumor activity in NHL and CLL xenografts, including Rituxan-refractory models. During profiling studies to confirm the reported expression of CD37 in normal tissues and B-cell malignancies, we made the novel discovery that the CD37 protein was expressed in T-cell lymphomas and in AML. AGS67E bound to >80% of NHL and T-cell lymphomas, 100% of CLL and 100% of AML patient-derived samples, including CD34+CD38− leukemic stem cells. It also induced cytotoxicity, apoptosis, and cell-cycle alterations 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 well expressed and a potential drug target in AML.

Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas

“…Finally, in addition to B-cell NHL, we and others 19 have detected CD37 expression in primary patient PTCL samples. However, not all the PTCL lines or primary samples tested were CD37 positive, indicating that CART-37 is likely to be useful for only some PTCL cases, underlining the importance of screening for CD37 expression in tumors of patients considering CD37-targeted therapy.…”

“…[20][21][22] CD37 represents a promising target for B-and T-cell lymphoma therapy, and recently has been validated as a druggable target, using monoclonal antibodies and antibody-drug conjugates in clinical trials of both B-and T-cell lymphoma. 19,23,24 Here, we confirmed expression of CD37 in B-and T-cell malignancies, generated a novel CAR targeting CD37, characterized its activity in a range of cells with varying levels of antigen density, and used a series of preclinical models to assess its efficacy. We demonstrate that CAR-37 engenders antitumor effect in vitro and leads to prolonged remissions in cell linebased and patient-derived xenograft (PDX) models of NHL.…”

“…17 Interestingly, recent studies have reported CD37 expression in cutaneous and peripheral T-cell lymphoma samples (CTCL and PTCL). 19 These patients have a poor prognosis and are underserved by current therapies, making this a high-priority set of diseases for the development of CAR T-cell approaches. [20][21][22] CD37 represents a promising target for B-and T-cell lymphoma therapy, and recently has been validated as a druggable target, using monoclonal antibodies and antibody-drug conjugates in clinical trials of both B-and T-cell lymphoma.…”

Advances in targeted therapy for malignant lymphoma

“…AGS67E has shown remarkable preclinical antitumor effects in NHLs and CLL cell lines and patient-derived xenograft models. 130 Clinically, a phase 1 study (NCT02175433) of escalating doses of AGS67E as monotherapy in relapsed or refractory lymphoid malignancies is ongoing. 177 Lu-lilotomab satetraxetan ( 177 Lu-DOTA-HH1, Betalutin®) is a novel antibody radionuclide conjugate (ARC) targeting the CD37 antigen.…”

Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions

“…CD37 is a member of the tetraspanin superfamily with expression limited to lymphoid tissues, particularly B cells [88,89]. CD37 expression in cancer cells is typically characteristic of B cell malignancies; however, its expression can be found in some cases CTCL and PTCL [90,91]. Since CD37 is not expressed in T cells, there is no evidence of fratricide occurring in anti-CD37 CAR T cells.…”