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.

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.

• Authors: Paul D Rennert, Fay J Dufort, Lihe Su, Tom Sanford, Alyssa Birt, Lan Wu, Roy R Lobb, Christine Ambrose
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 20 Issue 10 Pg. 2071-2081 (10 2021) ISSN: 1538-8514 [Electronic] United States
• PMID: 34253594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Antigens, CD19
• CD33 protein, human
• CLEC12A protein, human
• Lectins, C-Type
• Receptors, Mitogen
• Sialic Acid Binding Ig-like Lectin 3

Topics

• Animals
• Antigenic Drift and Shift
• Antigens, CD19 (immunology)
• Apoptosis
• Cell Proliferation
• Cytotoxicity, Immunologic (immunology)
• Humans
• Immunotherapy (methods)
• Immunotherapy, Adoptive (methods)
• In Vitro Techniques
• Lectins, C-Type (immunology)
• Leukemia, Myeloid, Acute (drug therapy, immunology, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Receptors, Mitogen (immunology)
• Sialic Acid Binding Ig-like Lectin 3 (immunology)
• T-Lymphocytes (immunology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays