TriTACs, a Novel Class of T-Cell–Engaging Protein Constructs Designed for the Treatment of Solid Tumors
| Autor: | Lemon Bryan D, Manasi Barath, Che-Leung Law, Robert B. Dubridge, Kenneth Sexton, Richard J. Austin, Stephen Yu, Timothy Yu, Purbasa Patnaik, Patrick A. Baeuerle, A. Jones, Anand Panchal, Luke Evnin, Russell Wall, Patricia Culp, Kathryn L. Strobel, Pui Seto, Vanitha Ramakrishnan, Holger Wesche, Wade Aaron, Sony Rocha |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research CD3 Complex T-Lymphocytes T cell Antineoplastic Agents Mice SCID Lymphocyte Activation CD19 03 medical and health sciences Prostate cancer 0302 clinical medicine Immune system Antigen Mice Inbred NOD Albumins Cell Line Tumor Neoplasms Animals Humans Medicine Cell Proliferation CD20 Cell Death biology business.industry Prostate-Specific Antigen medicine.disease Macaca fascicularis 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Antibody business Half-Life |
| Zdroj: | Molecular Cancer Therapeutics. 20:109-120 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T-cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This last modality is based on antibody constructs that bind a surface antigen on cancer cells and an invariant component of the T-cell receptor. Although high response rates were observed with T-cell engagers specific for CD19, CD20, or BCMA in patients with hematologic cancers, the treatment of solid tumors has been less successful. Here, we developed and characterized a novel T-cell engager format, called TriTAC (for Trispecific T-cell Activating Construct). TriTACs are engineered with features to improve patient safety and solid tumor activity, including high stability, small size, flexible linkers, long serum half-life, and highly specific and potent redirected lysis. The present study establishes the structure/activity relationship of TriTACs and describes the development of HPN424, a PSMA- (FOLH1-) targeting TriTAC in clinical development for patients with metastatic castration-resistant prostate cancer. |
| Databáze: | OpenAIRE |
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