MT-3724 is a new to immunotherapy from Molecular Templates, currently under investigation for the treatment of non-Hodgkin’s Lymphoma. This immunotoxin is based on Molecular Templates’ Engineered Toxic Bodies (ETBs) drug delivery platform and harnesses the immunotherapy power of receptor-specific targeting. MT-3724 demonstrates a unique mechanism of action, packing a cytotoxic 1-2-3 cancer killing punch.
MT-3724’s Mechanism of Action
While targeting CD20 antigens using anti-CD20 FAB fragments is nothing new for oncology treatments, Molecular Templates is using a completely new and revolutionary approach to initiate a cytotoxic immune response. The ETB platform is robust, combining multiple unique mechanisms into a single immunotoxin.
- It targets cancer cells using anti-CD FABs
- Tags cancer cells for an immune response using viral antigen
- Kill tumor cells by stopping ribosomal protein synthesis, effectively halting nuclear function.
Molecular Templates explains:
“Molecular Templates has developed an engineered toxin body (ETB) platform, a next-generation recombinant immunotoxin scaffold based on the Shiga-like toxin A subunit (SLT-1A) specifically directed to cancer cells via antibody fragment binding domains. The ETB scaffold is engineered to force the internalization of receptors that typically do not internalize or internalize poorly. Molecular Templates’ lead compound, MT-3724, is the first immunotoxin targeting CD20 to enter the clinic and is currently in a phase I study for refractory non-Hodgkin’s Lymphoma.
X-ray Crystallography Gallery
Additionally, we have taken advantage of the immunotoxin’s localization to the cytosol to engineer in a novel immuno-oncology mechanism of action. Molecular Templates’ Antigen Seeding Technology involves genetically fusing MHC class I antigens derived from human cytomegalovirus (HCMV) to the immunotoxin scaffold in order to mark these cells as targets for cytotoxic T lymphocyte (CTL) mediated cell lysis. Because antigen presentation does not require de novo protein synthesis, this mechanism of action is complementary to the inactivation of ribosomal function by the SLT-1 A domain of the ETBs. Since a large portion of the populace has a robust population of high-affinity effector T-cells targeting HCMV, the presentation of these antigens on ETB-intoxicated cancer cells may recruit a pre-existing CTL response to tumor cells. The recruitment of a CTL response has the potential to act additively or synergistically to the direct cell kill activity of the ETB and may expand the efficacy of these immunotoxins. “
MT-3724 Realtime 3D Explorer
Here we can see the anti-CD20 FAB light (yellow) and heavy (grey) chains bound to the CD20 Receptor (blue) lodged in a membrane. This is the natural orientation of CD20 and the FAB found in protein dataset 20SL. On top of the FAB complex is the ETB scaffolding. The Shiga-like Toxin is composed of two protein chains, A1 and A2. A1 (red) is the larger protein and is responsible for inactivating ribosomes. A2 (dark magenta) is the smaller protein. Grafted onto the Shiga-like Toxin is the Cytomegalovirus
Protein (dark purple). Click and drag the model below to rotate and explore the 3D structure.
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Feel free to email me if you have any questions ~ Casey Steffen M.Sci.