Molecular Templates to present four abstracts on pipeline data at AACR

Molecular Templates announced that new data on its pipeline programs and technology platform will be presented in four posters at the American Association of Cancer Research, or AACR, annual meeting. Preclinical data on TAK-169, the company’s CD38-targeted ETB, will be presented for the first time at the AACR meeting. This molecule is the most potent ETB that Molecular Templates has developed against any target to date. Importantly, in preclinical models, TAK-169 is active in the presence of daratumumab and active against daratumumab resistant cells. Molecular Templates will present on its CD38-targeted ETB, TAK-169. Although CD38 is a poorly internalizing receptor, TAK-169 is able to efficiently internalize and directly kill CD38-expressing cells. This novel mechanism of action may be relevant in 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. Furthermore, TAK-169 retains activity in the presence of excess approved, CD38 targeted therapeutic daratumumab. In xenograft models, complete regressions were observed using both a once-weekly and bi-weekly schedule of TAK-169. Tolerability studies in non-human primates demonstrate that repeat administration is tolerated at doses that are expected to be efficacious. TAK-169 is expected to enter the clinic in 2019. MT-3724 is a CD20-targeted ETB that has demonstrated single agent anti-tumor activity in heavily pre-treated relapsed/refractory Non-Hodgkin’s lymphoma, or NHL, patients in a Phase I clinical study. The combination of MT-3724 with chemotherapeutic agents or an immunomodulatory agent all demonstrated additive or synergistic cytotoxicity of NHL cell lines. Additional clinical studies to evaluate MT-3724 as single agent and in combination with gemcitabine and oxaliplatin or lenalidomide are underway and expected to generate data in 2019. Molecular Templates has developed PD-L1-targeting ETBs as an approach to directly target tumor cells and overcome resistance mechanisms against PD-1 and PD-L1 antibodies. The cytotoxicity delivered by PD-L1-specific ETBs is engineered to be independent of a requirement for tumor infiltrating lymphocytes, high tumor mutational burden, or modulatory effects of the tumor microenvironment. Further, the activity is not dependent on blockade of the PD-1/PD-L1 checkpoint axis. Thus, PD-L1-targeting ETBs represent a distinct class of therapeutics with direct cell-kill mechanism of action and ability for activity in patients who have progressed on current standard of care or checkpoint therapy. In this presentation, the company highlights the efficacy and safety profile of MT-6020, a human and cynomolgus cross-reactive, PD-L1 targeted, ETB. MT-6020 binds to cell lines expressing non-human primate PD-L1 and elicits cytotoxic responses comparable to those observed on human tumor target cells. Molecular Templates’ PD-L1 ETB, 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. Molecular Templates expects to initiate clinical development of the PD-L1-targeted-ETB in 2H19. To further expand the therapeutic benefit of its ETB platform, Molecular Templates is characterizing ETBs that are targeted through multiple binding domains. 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, and 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. By pairing the biology and potency of ETB-mediated killing with the expanded targeting possibilities afforded by bispecific molecules, Molecular Templates aims to develop a new class of therapeutics to benefit cancer patients.

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