Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo
Open Access
- 12 July 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 20 (10), 2071-2081
- https://doi.org/10.1158/1535-7163.mct-20-1030
Abstract
Refractory Acute Myeloid Leukemia (AML) remains an incurable malignancy despite the clinical use of novel targeted therapies, new antibody-based therapies and cellular therapeutics. Here we describe the preclinical development of a novel cell therapy that targets the antigen CLEC12A with a biparatopic bridging protein. Bridging proteins are designed as "CAR-T cell engagers", with a CAR-targeted protein fused to antigen binding domains derived from antibodies. Here, we created a CD19-anti-CLEC12A bridging protein that binds to CAR19 T cells and to the antigen CLEC12A. Biparatopic targeting increases the potency of bridging protein-mediated cytotoxicity by CAR19 T cells. Using CAR19 T cells that secrete the bridging protein we demonstrate potent activity against aggressive leukemic cell lines in vivo. This CAR-engager platform is facile and modular, as illustrated by activity of a dual-antigen bridging protein targeting CLEC12A and CD33, designed to counter tumor heterogeneity and antigen escape, and created without the need for extensive CAR T cell genetic engineering. CAR19 T cells provide an optimal cell therapy platform with well understood inherent persistence and fitness characteristics.Keywords
This publication has 51 references indexed in Scilit:
- Pre-transplant MRD predicts outcome following reduced-intensity and myeloablative allogeneic hemopoietic SCT in AMLBone Marrow Transplantation, 2014
- Acute myeloid leukemia stem cells and CD33-targeted immunotherapyBlood, 2012
- Functional Anatomy of T Cell Activation and Synapse FormationAnnual Review of Immunology, 2010
- Immunologic messenger molecules: Cytokines, interferons, and chemokinesJournal of Allergy and Clinical Immunology, 2010
- Natural Expression of the CD19 Antigen Impacts the Long-Term Engraftment but Not Antitumor Activity of CD19-Specific Engineered T CellsThe Journal of Immunology, 2010
- The novel AML stem cell–associated antigen CLL-1 aids in discrimination between normal and leukemic stem cellsBlood, 2007
- THE B7 FAMILY REVISITEDAnnual Review of Immunology, 2005
- C-Type Lectin-Like Molecule-1Cancer Research, 2004
- Acute and Long-Term Toxicities Associated with Gemtuzumab Ozogamicin (Mylotarg®) Therapy of Acute Myeloid LeukemiaClinical Lymphoma, 2002
- Lymphoid-Associated Antigen Expression by Acute Myeloid LeukemiaAmerican Journal of Clinical Pathology, 1996