Naratuximab emtansine (IMGN529; K7153A); Debio 1562 | Drug Description

Naratuximab emtansine (see: ADC Drugmap) also known as IMGN529 and Debio 1562 is an antibody-drug conjugate (ADC) or immunoconjugate that consists of a humanized IgG1 antibody K7153A against the cell-surface antigen CD37, a member of the tetraspanin superfamily of cell surface antigens found on B-cell malignancies, that is covalently linked via the uncleavable, maleimide-derived thioether-based linker SMCC to the maytansinoid DM1, with potential pro-apoptotic and cytotoxic activities.

The antibody moiety of IMGN529 binds to CD37 on tumor B cells and induces an antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), thereby showing pro-apoptotic activity. In addition, after the internalization of this agent and lysosomal degradation, the DM1 moiety binds to tubulin and inhibits tubulin polymerization and microtubule assembly, resulting in a disruption of microtubule activity and cell division, and eventually causing cell death in CD37-positive B cells. The investigational drug is in clinical trials for the potential treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, B-Cell Lymphomas.

CD37, a transmembrane glycoprotein, is overexpressed in B-cell malignancies. Compared to reducible, cleavable linkers, the non-reducible SMCC linker shows increased stability in plasma.

Tetraspanin
The tetraspanin CD37, which is a heavily glycosylated 40- to 52-kDa glycoprotein, belongs to a family of transmembrane proteins which play a major role in the organization of the plasma membrane. Given the potential role of CD37 in supporting tumor survival and immune evasion, an improved understanding of tetraspanin activity may be clinically valuable.[1]

An early attempts to develop a tetraspanin-targeted therapy for the treatment of hematological malignancies included a murine anti-CD37 monoclonal antibody (MoAb) MB-1 labeled with iodine 131 or 131I for the treatment of patients with advanced-, low- or intermediate-grade non-Hodgkin lymphoma (NHL) who failed conventional treatment. [2] Although these initial approaches were promising, targeting CD20 became a more favored approach. As result, the potential of CD37 as a target was, for many years, neglected. Recently, anti-CD37 therapies, including IMGN529, have seen a resurgence and are now actively investigated.[1]

Update: in 2017, as part of its strategic review, ImmunoGen has sold off its Phase 2-ready antibody-drug conjugate, IMGN529, to Swiss biopharma Debiopharm (Development code: Debio 1562).

Clinical trials
IMGN529 in Treating Patients With Relapsed or Refractory Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia – ClinicalTrials.gov ID NCT01534715 (Phase 1)

Reference
[1] Beckwith KA, Byrd JC, Muthusamy N. Tetraspanins as therapeutic targets in hematological malignancy: a concise review. Front Physiol. 2015 Mar 23;6:91. doi: 10.3389/fphys.2015.00091.
[2] Hicks SW, Lai KC, Gavrilescu LC, Yi Y, Sikka S, Shah P, Kelly ME, Lee J, Lanieri L, Ponte JF, Sloss CM, Romanelli A. The Antitumor Activity of IMGN529, a CD37-Targeting Antibody-Drug Conjugate, Is Potentiated by Rituximab in Non-Hodgkin Lymphoma Models. Neoplasia. 2017 Sep;19(9):661-671. doi: 10.1016/j.neo.2017.06.001. Epub 2017 Jul 25. PMID: 28753442; PMCID: PMC5540712.

Author: Peter Hofland, Ph.D

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