Debio 1562M | Drug Description

Debio 1562M is a next-generation investigational antibody-drug conjugate (ADC) being developed by Debiopharm, consisting of a humanized monoclonal antibody (K7153B[huCD37-3] or naratuximab) directed against CD37 and conjugated to a peptidic cleavable linker (Multilink™)* bearing a maytansinoid cytotoxic payload (DM1).**/^[1]

Linker chemistry
Debiopharm’s proprietary Multilink™, a linker chemistry which is selectively recognized and cleaved by the carboxydipeptidase activity of Cathepsin B, allows for high, homogeneous drug-to-antibody ratio (DAR~8), good solubility, high stability in systemic circulation and fast intracellular payload and catabolites release.

CD37
CD37, also known as TSPAN26 and GP52-40, is a trans-membrane protein member of the tetraspanin superfamily (characterized by their four transmembrane domains) widely expressed on malignant mature B cells including B-cell non-Hodgkin lymphoma (NHL) and B-cell chronic lymphocytic leukemia (B-CLL).

The CD37 receptor acts as a signal modulator for diverse physiological functions and has been described to regulate migration, endocytosis, cell survival, and immune response among others.

CD37 expression in normal, healthy, tissue is highly restricted to hematopoietic cells. Primarily described on B cells, CD37 is strongly expressed and plays important roles in their development and modulation their immune function.[2] Only weak expression is observed on T cells, myeloid cells, and granulocytes [3][4][5]

CD37 is absent on other hematopoietic cells including hematopoietic stem cells, pro-B cells and normal plasma cells.

CD37 in cancer
In cancers, CD37 antigen is over-expressed on B cell non-Hodgkin lymphoma (NHL) including diffuse large B‑cell lymphoma (DLBCL), [6] follicular lymphoma (FL),[7] mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL) subtypes.[8][3]

In acute myeloid leukemia (AML), which is characterized by the accumulation of immature myeloid cells in the bone marrow and the peripheral blood, increased CD37 expression on blasts and leukemic stem cells has also been reported, both at protein and mRNA levels.  [9][10]11][12] This increased expression is restricted to malignant cells compared to hematopoietic stem cells [11] and correlates with poor patient outcome. [13][14] The internalization properties of CD37 are distinct in AML blasts when compared to normal blood cells, with CD37 rapidly accumulating inside AML blasts via dynamin-dependent endocytosis. [14]

Toxicology
Safety and pharmacodynamic data from preclinical studies with Debio 1562M in Acute myeloid leukemia were presented in a poster presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition being held December 9 – 12, 2023 in San Diego, CA.[1]

Although a toxicology profile of Debio 1562M in mice demonstrated expected clinical signs related to the maytansinoid (DM1) payload’s off target toxicity, researchers observed a significant safety margin without peripheral neuropathy symptoms commonly observed for this class of payload. Furthermore, the Multilink™-payload construct alone was not associated with any signs of toxicity.[1]

Taken together, these results suggest that CD37 represents a relevant therapeutic target for the treatment of all AML subtypes.

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Note: * Debiopharm’s peptidic cleavable linker, Multilink™, is a linker which is selectively recognized and cleaved by the carboxydipeptidase activity of Cathepsin B, one of the most versatile human cysteine cathepsins. This linker system allows highly efficient and selective drug release. It is also stable in plasma and it enables the preparation of ADCs with high drug-to-antibody ratio (DAR).[15][16][17][18]

** Maytansine and its derivatives, which are collectively known as maytansinoids or DMs, are a class of highly potent and cytotoxic benzoansamacrolides microtubule polymerization inhibitors, belonging to the macrolide family and are closely related to the ansamycin group of antibiotic compounds. Their defining feature is a 19-member ansa macrolide structure, also known as maytansine, which is covalently linked to a chlorinated benzene ring chromophore. They suppress microtubule dynamics to preferentially kill dividing versus quiescent cells, typically with concentrations that give 50% inhibition (IC₅₀values) in the sub-nanomolar range. By disrupting the microtubule network—a fundamental component of the cell cytoskeleton essential for cell divisio—they effectively induce apoptosis in cancer cells. Maytansine was first isolated from Maytenus serrata and Maytenus buchananii in the late 1970s and early 1980s. [19][20][21]

^DM1 is also called mertansine (and in some of its forms emtansine).

Reference
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Author: Peter Hofland, Ph.D

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