On April 12, 2021 Molecular Templates, Inc. (Nasdaq: MTEM, "Molecular Templates," or "MTEM"), a clinical-stage biopharmaceutical company focused on the discovery and development of proprietary targeted biologic therapeutics, engineered toxin bodies (ETBs),reported that three posters featuring data on its pipeline programs and technology platform will be presented at the AACR (Free AACR Whitepaper) Virtual Annual Meeting I, taking place April 10-15, 2021 (Press release, Molecular Templates, APR 12, 2021, View Source [SID1234577919]).
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Title: Phase 1 Study of the Novel Immunotoxin MT-5111 in Patients with HER2+ Tumors
Authors: Zev A. Wainberg, MD; Monica M. Mita, MD; Minal A. Barve, MD; Erika P. Hamilton, MD; Andrew J. Brenner, MD, PhD; Frances Valdes, MD; Daniel Ahn, DO; Joleen Hubbard, MD; Jason Starr, DO; Christine Burnett, PhD; Joshua Pelham; Eric T. Williams, PhD; Aimee Iberg, PhD; Thomas Strack, MD; Andrés Machado Sandri, MD; Brian A. Van Tine, MD, PhD
Abstract # CT130
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.
Title: Preclinical Characterization of a Novel CTLA-4-Targeted ETB for Direct Treg Depletion
Authors: Khanna, Caleigh Howard, Lilia A. Rabia, Alvaro Aldana, Jay Zhao, Asis Sarkar, Eric Williams, Banmeet Anand, Betty Chang, Chris Moore, Hilario J. Ramos, Aimee Iberg — Molecular Templates Inc., Austin, TX.
Abstract # 1627
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.
Title: Engineered Toxin Bodies Targeting PD-L1 to Alter Tumor Immunophenotypes and Delivery Broad Antigenic Diversity and Patient Coverage
Authors: Swati Khanna, Elizabeth Saputra, Wenzhao Dong, Lindsey Aschenbach, Lilia A. Rabia, Garrett L. Cornelison, Michaela Sousares, Jay Zhao, Lee Robinson, Betty Chang, Hilario J. Ramos, Joseph D. Dekker
Molecular Templates Inc., Austin, TX
Abstract # 1628
MT-6402 is an ETB designed to deliver a unique and dual mechanisms of action approach for directly targeting tumors that express PD-L1 on the tumor and/or the TME. Unlike current checkpoint inhibitors which only bind PD-L1 and sterically block interactions with PD-1, MT-6402 directly destroys PD-L1+ tumor and TME immune cells. MT-6402 has dual mechanisms of action that include the enzymatic destruction of ribosomes and the delivery of a viral class I antigen derived from CMV (pp65) into the targeted tumor, referred to as Antigen Seeding Technology (AST), for presentation on the target tumor cell surface to alter the tumor immunophenotype and induce a CMV specific T-cell response. MT-6402’s antigen seeding CMV pp65 payload covers the largest MHC haplotype in the US. Delivery of foreign antigens that are restricted to additional MHC haplotypes could broaden the patient population that could benefit from AST. ETBs based on MT-6402 that deliver additional antigens retain expected potency and target binding, while also activating donor CTLs with matched haplotypes. ETBs delivering antigens to a broader population are under investigation for in vivo safety, efficacy and function. The MT-6402 IND filing has been accepted by the FDA with the Phase 1 first-in-human study expected to begin dosing in 2Q21.