Molecular Templates, Inc. reported that three posters featuring data on its pipeline programs and technology platform will be presented at the AACR Virtual Annual Meeting I, taking place April 10-15, 2021. This poster summarizes results from a data cut in December 2020 for an ongoing Phase 1, first in human, open-label, dose escalation and expansion study of MT-5111 in subjects with HER2+ solid tumors. MT-5111 has a novel mechanism of action that may not be subject to resistance mechanisms that exist for current HER2 therapies, binds a distinct epitope on HER2 that allows for potential combination with trastuzumab-based therapies, and, at 55kDa, is significantly smaller than other HER2 antibody or ADC therapies. As of the data cut in December 2020, 16 study subjects had been treated in the 3+3 cohort escalation. The cancer types included biliary tract (n=6), breast (n=6), pancreatic (n=2), gastric (n=1), and colon (n=1). Results to date show that MT-5111 has been well tolerated at escalated doses up to Cohort 5 (4.5 µg/kg), which allowed for the progression to Cohort 6 (6.75 µg/kg). There have not been any dose limiting toxicities nor any signs of cardiotoxicity to date, and the MTD has not been reached. Pharmacokinetic data for the first 5 cohorts matched simulations based on non-human primate studies. Exposures at 4.5 µg/kg have reached approximately 5x the IC 50 of HER2-expressing cell lines. Three patients experienced stable disease as best response per RECIST 1.1 criteria (1 pancreatic at 4.5 µg//kg, 1 breast at 2 µg//kg, 1 biliary tract at 2 µg/kg). As previously reported, one subject with metastatic breast cancer in cohort 2 (1 µg/kg) remained on treatment for 10 cycles with stable disease; although she had unmeasurable disease by RECIST criteria, she had three sub-centimeter hepatic lesions that disappeared at the end of cycle 8 before she discontinued for clinical progression/symptomatic deterioration at cycle 10. This subject had received three prior HER2 targeting regimens which initially included pertuzumab plus trastuzumab followed by trastuzumab and TDM1 as monotherapies. Dose escalation continues and no dose limiting toxicities have been observed to date at 6.75 µg/kg (Cohort 6). The HER2+ breast cancer expansion cohort is planned to be initiated in 2Q21 at a dose of 10 µg/kg (anticipated to be a therapeutic dose level), pending adequate safety from the 10 µg/kg dose escalation cohort. Dose escalation in all HER2+ tumor types will continue (including potential cohorts beyond 10 µg/kg) to determine the recommended Phase 2 dose while the breast cancer expansion cohort collects efficacy and safety data. As doses higher than 10 µg/kg are considered to be tolerable in the dose escalation cohort, the dose will be increased in the breast cancer cohort accordingly. Current CTLA-4 antibodies have shown efficacy in oncology but have been limited by toxicity issues and an inability to clear regulatory T cells (Tregs) from the tumor microenvironment (TME). CTLA-4-targeted ETBs are designed to preferentially deplete Tregs in the TME to improve efficacy and reduce the toxicity associated with CTLA-4 targeted antibodies. This study explored the preclinical characterization of a lead candidate CTLA-4-targeted ETB. CTLA-4-ETB-A directly binds and specifically kills CTLA-4 positive cells in vitro and induces apoptosis of ex-vivo expanded Tregs. CTLA-4-ETB-A is designed to bind CTLA-4 in a manner unique from classic blocking antibodies and is not expected to have sustained blocking ability in vivo due to the relatively short half-life of an ETB compared to a neutralizing monoclonal antibody. The authors predict this will allow for focused Treg depletion in the TME based on target expression levels, while sparing autoreactive T cell activation in the periphery to reduce or eliminate the toxicity seen with CTLA-4 antibodies. In a transgenic mouse model expressing human CTLA-4 and bearing syngeneic subcutaneous tumors, CTLA-4 expression was highest on the Treg cells within the tumor microenvironment compared to other T cell populations and compartments. In this model, it was demonstrated that ETB treatment depletes Tregs in the TME, supporting the overall hypothesis. Peripheral CD4+ T cell proliferation was observed in response to ETB treatment. Initial tox assessment was performed in a non-human primate (NHP) model. ETB candidate A was well tolerated up to 450 µg/kg. An increase in proliferating CD4+ and CD8+ central memory T cells was observed and is a potential pharmacodynamic effect.