The HER2 receptor is overexpressed in 20-30% of breast cancers. HER2 overexpression in breast cancer has been successfully targeted by both antibody and antibody-drug conjugate (ADC) approaches. The recently approved trastuzumab-emtansine (T-DM1, Kadcyla) ADC has shown promising clinical results in patients refractory to trastuzumab (Herceptin). Because DM1 is a chemotherapeutic and refractory breast cancer patients have typically progressed through several rounds of chemotherapy, we are developing a new targeted therapy approach utilizing a novel mechanism of action. MT-2H74 is an engineered toxin body comprised of the trastuzumab single chain variable fragment (scFv) and a modified ribosome-inactivating protein derived from Shiga-like toxin 1 A (SLT-1A). We have proprietarily modified SLT-1A for reduced immunogenic potential and increased stability. MT-2H74 selectively binds HER2-expressing breast cancer cells, and exerts a potent HER2-specific cytotoxic effect on several tested cell lines. MT-2H74 demonstrates effective cell kill at picomolar concentrations on cell lines expressing high levels of HER2 and is not cytotoxic to HER2 negative control cell lines. Multi-drug resistance transporter 1 (MDR1) has been reported to confer resistance to chemotherapeutic and ADC treatments, such as direct T-DM1 cell kill; however, MT-2H74 displays cytotoxic activity against HER2 transfected NCI/ADR-RES cells known to express MDR1. Murine models are under investigation to determine therapeutic efficacy in vivo. MT-2H74 is a promising HER2-targeted therapeutic agent against breast carcinomas with a unique mechanism of action and is currently under further development. Citation Format: Erin K Willert, Sangeetha Rajagopalan, Garrett L Robinson, Brigitte Brieschke, Jennifer Erdman, William Null, Jack P Higgins. A novel targeted engineered toxin body for treatment of HER2 positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-17.
Molecular Templates has developed engineered toxin bodies (ETBs), potent recombinant immunotoxins that combine the specificity of an antibody fragment with the powerful direct cytotoxicity of the Shiga-like toxin A subunit to specifically destroy target expressing cells. The use of other immunotoxins and antibody-drug conjugates is limited to targets with tumor-specific cell surface expression that efficiently internalize. The ETB scaffold has been designed to overcome this limitation and promote forced internalization of ETBs, a property that expands the potential targets to receptors with poor internalization kinetics. An additional benefit to ETBs is the mechanism of action (MOA) which is unique to that of other oncology treatments. CD20, a receptor that does not undergo rapid internalization, is a well characterized target for agents used to treat non-Hodgkin's lymphoma (NHL). Thus, successful CD20-targeted clinical strategies include monoclonal antibodies (mAbs) and radiolabeled mAbs that act on the cell surface. Molecular Templates’ lead compound, MT-3724, is a CD20-targeted ETB that has been engineered to force the rapid internalization of the immunotoxin after binding to CD20. MT-3724 has potent direct cell kill activity on CD20 positive lymphoma cells and is the first immunotoxin to CD20 to enter the clinic. The on-going phase I study being conducted at Memorial Sloan-Kettering Cancer Center, MD Anderson Cancer Center, and New York University Langone Medical Center has shown promising safety and efficacy in highly refractory NHL patients. Once MT-3724 is delivered to appropriate cells, the Shiga toxin A subunit inhibits protein synthesis and promotes apoptosis of tumor cells. The difference in MOA allows for activity in the refractory setting, where resistance to other treatments has emerged, and may also allow for combination therapy. Pre-clinical studies with immunomodulatory drugs (IMiDs), PI3K and Bcl-2 inhibitors that are used in treatment of NHL have shown promising results when combined with MT-3724. MT-3724 is a promising novel agent in the treatment of NHL and other CD20 positive hematological malignancies. Data around the internalization kinetics, enzymatic activity, and combination with other agents will be presented. Citation Format: Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jennifer Erdman, Jane Neill, Rodney E. Flores-Lefranc, Julia Foree, William Null, Jensing Liu, Jack P. Higgins, Erin K. Willert. MT-3724, an engineered toxin body targeting CD20 for non-Hodgkin's lymphoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1483.
Engineered toxin bodies (ETBs) comprised of a proprietarily engineered Shiga-like Toxin A subunit (SLTA) genetically fused to antibody-like binding domains work through novel mechanisms of action and can force internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Our PD-L1 targeted ETB, MT-6402, includes antigen seeding technology (AST), and additionally delivers a viral antigen for presentation in complex with MHC-I to resident viral-specific cytotoxic T lymphocytes (CTLs). The fusion protein provides a powerful, dual mechanism of action to specifically target and destroy PD-L1 positive tumor and inhibitory immune cells. In vitro testing of human tumor cell lines has demonstrated that cell surface PD-L1 expression is required for activity of the PD-L1 targeted ETBs. MT-6402 demonstrated effective depletion of PD-L1 expressing cells across a panel of immortalized cancer cell lines from multiple origins, including lung, skin, breast, and ovary. In a co-culture assay of PD-L1 target cells and antigen specific T-cells, PD-L1 targeted MT-6402 delivers a viral antigen to the target cells and can activate cytokine secretion and T-cell mediated killing. Additionally, MT-6402 treatment of human peripheral blood mononuclear cells (PBMCs) leads to selective depletion of PD-L1 positive cells (IFN-γ stimulated monocytes) in the absence of depletion of PD-L1 low/negative lymphocytes. Murine models, including patient derived xenografts, have demonstrated that the PD-L1 targeted ETBs are efficacious in vivo. Additional in vivo tumor models to further describe the effect of MT-6402 are being explored. Exploratory studies in a primate model have shown that MT-6402 can be tolerated at levels shown to induce T cell activation (type 1 cytokines). MT-6402 delivers a powerful and unique dual mechanism of action. The combination of a PD-L1 specific direct cell kill and redirection of a robust effector T cell response to the tumor has potential benefit in solid tumor indications, including in the relapsed setting, when disease has progressed after checkpoint and/or other therapies. Citation Format: Hilario J. Ramos, Brigitte Brieschke, Sara LeMar, Joseph D. Dekker, Aimee Iberg, Garrett L. Robinson, Asis Sarkar, Banmeet Anand, Melissa M. Singh, Jay Zhao, Jack P. Higgins, Erin K. Willert. In vivo efficacy of a PD-L1 targeted, antigen seeding engineered toxin body [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3366.
Molecular Templates is developing engineered toxin bodies (ETBs), potent recombinant immunotoxins that combine the specificity of an antibody fragment with the powerful direct cytotoxicity of the Shiga-like toxin A subunit (SLTA). ETBs can induce their own internalization, route through the cell in a predictable manner, enzymatically and irreversibly destroy ribosomes to shutdown protein synthesis and induce apoptosis of tumor cells. This mechanism of action is distinct from that of other therapeutics, making ETBs an attractive treatment for patients who have become resistant to chemotherapy and other treatments. Safety and efficacy in refractory non-Hodgkin’s lymphoma patients has been observed in a phase I study with Molecular Template’s first-generation CD20-targeting compound, MT-3724. CD38 is a surface receptor that is highly expressed on malignant plasma cells. CD38 is a clinically validated target of monoclonal antibodies for treatment of multiple myeloma and is known to persist after failure of antibody treatment. MT-4019 is a CD38-targeted next-generation ETB, utilizing a modified SLTA. The SLTA subunit of the next-generation ETB scaffold has been modified through proprietary genetic engineering to systematically and comprehensively reduce B cell and CD4+T cell epitopes, as well as to dampen the innate response by decreasing binding to TLR-4. This de-immunized next-generation scaffold retains the potency and specificity of an ETB containing an unmodified SLTA. Pre-clinical studies in rodents and non-human primate models have demonstrated the tolerability of MT-4019, along with a decreased anti-drug antibody response. Additionally, in the non-human primate model, MT-4019 showed reduced neutrophil and monocyte activation as compared to an ETB with an unmodified SLTA subunit, indicating that SLTA modification also exhibits a diminished innate immune response. Molecular Template’s ETB technology has resulted in potent, targeted therapeutic agents that have a unique mechanism of action in the field of oncology. MT-3724, a first-generation CD20-targeted ETB, has shown promising clinical results in the refractory setting for non-Hodgkin’s lymphoma. The next-generation scaffold, as exemplified in the CD38-targeted MT-4019, retains potent and specific direct cell kill activities, and additionally reduces the innate and adaptive immune response to the therapeutic. MT-4019 is a promising lead and is under further development to enable clinical studies in multiple myeloma. Citation Format: Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jane Neill, Jennifer Erdman, Rodney Flores, Jensing Liu, Jack P. Higgins, Erin K. Willert. MT-4019: a de-immunized engineered toxin body targeting CD38 for multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2659. doi:10.1158/1538-7445.AM2017-2659
12 Background: Engineered toxin bodies (ETBs) comprised of a proprietarily engineered Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains work through novel mechanisms of action and can force internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Our PD-L1 targeted ETB includes antigen seeding technology (AST), and additionally delivers a viral antigen for presentation in complex with MHC-I to resident viral-specific cytotoxic T lymphocytes (CTLs). The fusion protein provides a powerful, dual mechanism of action to specifically target and destroy PD-L1+ tumor and inhibitory immune cells. Methods: In vitro activity of ETBs was measured by cell viability and kinetic imaging of labeled target cells in an effector T-cell co-culture assay. Repeat dosing in non-human primates (NHPs) and murine models harboring human PD-L1+ patient derived tumors were used to evaluate tolerability and efficacy. Results: ETBs targeting PD-L1 have potent direct and specific activity across human tumor cell lines and human donor derived monocytes expressing PD-L1 in vitro. In co-culture assays, AST capable ETBs had a deeper response when target cells express both PD-L1 and the appropriate MHC-I allele in the presence of antigen specific CTLs. In vivo, PD-L1 targeted ETBs induced tumor growth delay, regression and survival benefit in multiple PD-L1+ NSCLC PDX models. These ETBs were also tolerated in repeat dosing NHP studies. Conclusions: The potent targeted activity of ETB mediated tumor cell destruction is demonstrated across tumor cell lines from multiple indications, on PD-L1+ immune cells ex-vivo, and by tumor growth and survival benefits in PDX models in vivo. The AST capable, PD-L1 targeted ETBs provide dual novel mechanisms to deplete PD-L1+ cells and control malignancies. Both the SLT-A mediated direct cell kill and activation of viral-specific CTLs circumvents a need for high mutational burden or anti-tumor immune-cell infiltrate at the tumor site, providing a potential treatment option for patients whose disease has progressed after checkpoint therapy.
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