On April 12, 2022 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 highlights from the six poster presentations on its pipeline programs that were presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, taking place April 8 – April 13, 2022 at the Ernest N. Morial Convention Center in New Orleans, LA (Press release, Molecular Templates, APR 12, 2022, View Source [SID1234612074]). Copies of the posters presented at AACR (Free AACR Whitepaper) can be found in the Investors section of Molecular Templates’ website under Presentations.
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"We believe that ETBs offer novel biology that have the potential to translate into unique clinical outcomes, even against well-explored targets," said Eric Poma, Ph.D., CEO and CSO of Molecular Templates. "We are seeing differentiated pharmacodynamic effects in patients in our Phase I study with MT-6402, our PD-L1 targeting agent, from both that agent’s direct cell-kill effects and its antigen seeding ability. We believe we can leverage this unique biology across other targets such as CTLA-4, TROP-2, and TIGIT."
Poster Title: A Phase 1 Study of MT-6402, a novel Engineered Toxin Body (ETB) targeting PD-L1, in patients with PD-L1 expressing advanced solid tumors
Authors: David R. Spigel, MD; Eugene Ahn, MD, PhD; John D. Powderly, Herbert L. Duvivier, JD, MD; Drew Rasco, MD; Agnes Rethy, MD; Chris Moore, PhD; Amy Yuet, PhD; Angela Georgy, PharmD; Sandra R. Hankins; Swati Khanna, PhD; Joseph D. Dekker, MD; Brian A. Van Tine, MD
Abstract #: 7936
Poster highlights:
Twelve patients with PD-L1+ relapsed/refractory disease have been treated to date across two dose cohorts: 16 mcg/kg (n=6) and 24 mcg/kg (n=6).
Pharmacodynamic (PD) effects including monocyte and myeloid-derived suppressor cell depletion and T cell activation have been observed in the majority of patients. The extent and timing of these PD effects appear dose-related with patients in the 24 mcg/kg cohort generally showing a more rapid and profound PD effect.
One patient in the first cohort with non-small cell lung cancer (NSCLC) (osseous non-measurable disease only) that had progressed after prior checkpoint therapy (PD-1 and CTLA-4) showed qualitative reduction in tumor burden.
One dose-limiting toxicity (DLT) was observed in a single patient (24 mcg/kg). The patient experienced dermatitis that resolved rapidly with systemic steroids. The patient was rechallenged without incident at 24 mcg/kg. No other DLTs have been reported.
Poster Title: Altering tumor immunophenotypes with PD-L1 engineered toxin bodies
Authors: Swati Khanna, Elizabeth M. Kapeel, Lauren R. Byrne, Elizabeth Saputra, Steven Rivera, Lindsey Aschenbach, Lilia A. Rabia, Garrett L. Cornelison, Rachael M. Orlandella, Brigitte Brieschke, Michaela Sousares, Jay Zhao, Garrett L. Robinson, Chris B. Moore, Joseph D. Dekker
Abstract #: 3543
Poster highlights
Molecular Templates’ Antigen Seeding Technology (AST) is a unique approach that allows for specific alteration of tumor immunophenotype to match pre-existing CD8+ T-cells in a patient. This approach is currently being tested clinically with MT-6402, a PD-L1 targeted ETB that delivers an HLA-A2 antigen derived from cytomegalovirus (CMV).
Data are presented here demonstrating that MT-6402 can be altered to present antigens derived from CMV corresponding to other HLA genotypes, thereby broadening the potential patient population that could benefit from this approach.
Poster Title: A CTLA-4-targeted ETB for Treg depletion shows favorable preclinical efficacy and safety
Authors: Asis Sarkar, Rebecca Martin, Lauren R. Byrne, Kiheon Baek, James Pazar, Caleigh Howard, Swati Khanna, Lilia A. Rabia, Diana Adhikari, Michaela M. Sousares, Alvaro Aldana, Abdul G. Khan, Garrett L. Robinson, Jay Zhao, Chris B. Moore, Aimee Iberg
Abstract #: 3538
Poster highlights:
CTLA-4-targeted ETBs are designed to preferentially deplete regulatory T cells (Tregs), via a direct cell kill mechanism of action that is independent of effector cells, in the tumor microenvironment (TME) to improve efficacy and reduce the toxicity associated with CTLA-4 targeted antibodies.
In a transgenic mouse model expressing human CTLA-4 and bearing syngeneic subcutaneous tumors, CTLA-4 ETB treatment depleted Tregs in the TME.
CTLA-4 ETB candidate was well tolerated in a non-human primate toxicology study.
Overall, these preclinical data support the use of ETB technology to deplete immune suppressive regulatory T cells in the TME to allow immune reactivation to tumor.
Poster Title: Engineered Toxin Bodies (ETBs) targeting Trop2
Authors: Garrett L. Cornelison, Adam Bartos, Brigitte Brieschke, Jessica Momb, Ileana Pedraza, Elizabeth M. Kapeel, Rebecca Martin, Channing Pletka, Adrian Gonzalez, Joseph D. Dekker, Jay Zhao, John Majercak, Garrett L. Robinson.
Abstract: #326
Poster highlights:
Trop2 targeted ETBs show in vitro target specific picomolar potency on Trop2 positive tumor cell lines.
AST enabled Trop2 targeted ETBs to retain direct cell kill potency and alter the tumor immunophenotype to allow for antigen specific T-cell recognition.
Final lead selection based on evaluation of additional targeting domains and AST antigens is underway.
Poster Title: Improving immunotoxin-based therapeutics for cancer with de-immunized Engineered Toxin Bodies
Authors: Rachael M. Orlandella, Elizabeth M. Kapeel, Swati Khanna, Brigitte Brieschke, Garrett L. Robinson, Joseph D. Dekker, and Chris B. Moore
Abstract #: 2579
Poster highlights:
Molecular Templates has developed a de-immunized form of Shiga-like Toxin A (SLTA), incorporated into next-generation ETBs currently in clinical trials, that has demonstrated a lack of innate immune activation and capillary leak syndrome (CLS) in animal models and patients.
Ex vivo assays using peripheral blood mononuclear cells (PBMCs) demonstrate that unmodified SLTA displays upregulation of CCL3, CCL4, TNFα and IL-6, indicating a similar, but not identical, pattern of cytokine release relative to the positive control, lipopolysaccharide (LPS), while the de-immunized SLTA did not activate cytokine or chemokine release.
These data help confirm the observations in animal models and patients that indicate the de-immunized SLTA scaffold lacks the ability to trigger innate immunity seen with unmodified SLTA used in first generation ETBs.
Poster Title: C-KIT/CD117 targeted ETBs for cancer therapy and HSC transplant conditioning
Authors: Caleigh Howard, Shu Wiley, Wenzhao Dong, Andrea Mendiola, Veronica Partridge, Antonio Luz, Sara LeMar, Paul Amador, Amit Kumar Chaudhary, Joseph D. Dekker, Jay Zhao, Ross Durland, Aimee Iberg
Abstract #: 335
Poster highlights:
Molecular Templates has developed CD117 targeting ETBs that may have potential uses in myeloablation or in oncology.
CD117 ETB drug conjugates with MMAF demonstrated increased cytotoxicity compared to stand-alone ETBs or inactive ETB drug conjugate controls and also highlighted the internalization augmenting capabilities of ETBs.