Molecular Templates’ Presentations at the American Association of Cancer Research (AACR) Annual Meeting 2019 Highlight Evolution of ETB Platform
“We believe that ETBs represent an important advance in immunotoxins as a therapeutic class of drugs. MT-3724 has demonstrated forced internalization of CD20 and has driven responses in heavily pretreated DLBCL patients. While MT-3724 development continues in Phase II, our presentations at AACR highlight next generation pipeline programs that show key improvements in the ETB platform,” said
|Poster Title: TAK-169, an Exceptionally Potent CD38 Targeted Engineered Toxin Body, as a Novel Direct Cell Kill Approach for the Treatment of Multiple Myeloma|
- TAK-169 is able to efficiently internalize and directly kill CD38-expressing cells with potency seen at picomolar or sub-picomolar concentrations.
- Preclinical data suggest that TAK-169 may provide benefit to patients who have progressed after or are unlikely to respond to CD38-targeted antibody therapy.
- TAK-169 has demonstrated potent cytotoxicity across a range of myeloma cell lines with a range of CD38 expression in vitro as well as in patient-derived samples including those with previous exposure to daratumumab.
- TAK-169 retains activity in the presence of daratumumab.
- In xenograft models, complete regressions were observed using both once-weekly and bi-weekly schedules of TAK-169.
- TAK-169 was tolerated in cynomolgus monkeys (highest non-severely toxic dose [HNSTD] of 750 mcg/kg weekly) at doses where evidence of pharmacodynamic effect (NK cell depletion) was observed. In comparison, the HNSTD of MT-3724 was 150 mcg/kg with visible signs of capillary leak syndrome (CLS); dosing MT-3724 at 450 mcg/kg showed severe CLS in cynomolgus monkeys.
|Poster Title: The Safety and efficacy Profile of a PD-L1-Directed, Engineered Toxin Body, as a Novel Targeted Direct-Cell Kill Approach for the Treatment of PD-L1-Expressing Cancers|
Molecular Templateshas developed PD-L1-targeting ETBs as an approach to directly target tumor cells and overcome resistance mechanisms against PD-1 and PD-L1 antibodies.
- MT-6020, a human and cynomolgus cross-reactive, PD-L1-targeted, ETB binds to cell lines expressing non-human primate PD-L1 and elicits cytotoxic responses comparable to those observed on human tumor target cells.
- MT-6035 is built upon the MT-6020 scaffold and can also deliver a viral peptide for cell surface presentation and targeting by a specific antiviral CTL population for a second and complementary mechanism for tumor cell destruction, referred to as antigen seeding.
- MT-6020 and MT-6035 represent a novel approach to targeting and destroying tumors expressing PD-L1 that is unlikely to be inhibited by resistance mechanisms to current checkpoint inhibitors, is well tolerated in relevant toxicity models, and has the capacity for activity in indications where standard of care has failed.
|Poster Title: Combination of CD20-targeted Engineered Toxin Body, MT-3724, with Chemotherapy or IMiDs for the Treatment of Non-Hodgkin's Lymphoma|
- MT-3724, a CD20-targeted ETB, has demonstrated single agent anti-tumor activity in heavily pre-treated relapsed/refractory (R/R) non-Hodgkin’s lymphoma (
NHL) patients in a Phase I clinical study.
- The combination of MT-3724 with chemotherapeutic agents (doxorubicin, gemcitabine, bendamustine, and vincristine) or an immunomodulatory (IMiD) agent (lenalidomide) all demonstrated additive or synergistic cytotoxicity of
- Clinical studies to evaluate MT-3724 as single agent and in combination with gemcitabine and oxaliplatin (GEMOX) or lenalidomide are underway and expected to generate data in 2019.
|Poster Title: Design and Characterization of Bispecific Engineered Toxin Bodies for Targeted Cancer Therapy|
- Bispecific ETBs that target two epitopes on the same receptor, or two distinct cell surface molecules both expressed on cancer cells, may allow for enhanced activity profiles. These possibilities include:
- activity in the presence of a competitive binding protein
- sustained activity when one target molecule is shed or downregulated
- synergistic binding events to increase overall potency
- increased specificity towards cancer over normal tissue.
- Bispecific ETBs have been generated to engage a variety of target combinations, relevant to both solid and hematologic cancer treatment.
- MTEM is exploring therapeutically relevant target combinations to facilitate the development of a bispecific clinical lead.
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Source: Molecular Templates, Inc.