COBRA™: a highly potent conditionally active T cell engager engineered for the treatment of solid tumors
| Autor: | Maia Vinogradova, Danielle E. Dettling, Russell Wall, Jessica L. Krakow, Aakash Datt, Elizabeth Pongo, Tseng-Hui T Chen, Andisheh Bagheri, Brian J. Hillier, Patricia Culp, Ying Zhu, Chad May, Robert B. Dubridge, Jeremiah D. Degenhardt, Pui Seto, Anand Panchal |
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| Rok vydání: | 2020 |
| Předmět: |
T cell receptor complex
T cell engager T-Lymphocytes EGFR T cell CD3 Immunology Cobra Mice SCID bispecific Matrix metalloproteinase Lymphocyte Activation Protein Engineering complex mixtures Jurkat Cells Mice 03 medical and health sciences Antineoplastic Agents Immunological 0302 clinical medicine Antigen Antigens Neoplasm Mice Inbred NOD Report Antibodies Bispecific medicine Animals Humans Immunology and Allergy COBRA 030304 developmental biology computer.programming_language 0303 health sciences Tumor microenvironment Solid tumor biology Chemistry conditional protease activated Neoplasms Experimental Prodrug Xenograft Model Antitumor Assays medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research biology.protein Immunotherapy HT29 Cells computer |
| Zdroj: | mAbs article-version (VoR) Version of Record |
| ISSN: | 1942-0870 1942-0862 |
| Popis: | Conditionally active COBRA™ (COnditional Bispecific Redirected Activation) T cell engagers are engineered to overcome the limitations of inherently active first-generation T cell engagers, which are unable to discern between tumor and healthy tissues. Designed to be administered as prodrugs, COBRAs target cell surface antigens upon administration, but engage T cells only after they are activated within the tumor microenvironment (TME). This allows COBRAs to be preferentially turned on in tumors while safely remaining inactive in healthy tissue. Here, we describe the development of the COBRA design and the characterization of these conditionally active T cell engagers. Upon administration COBRAs are engineered to bind to tumor-associated antigens (TAAs) and serum albumin (to extend their half-life in circulation), but are inhibited from interacting with the T cell receptor complex signaling molecule CD3. In the TME, a matrix metalloproteinase (MMP)-mediated linker cleavage event occurs within the COBRA construct, which rearranges the molecule, allowing it to co-engage TAAs and CD3, thereby activating T cells against the tumor. COBRAs are conditionally activated through cleavage with MMP9, and once active are highly potent, displaying sub-pM EC50s in T cell killing assays. Studies in tumor-bearing mice demonstrate COBRA administration completely regresses established solid tumor xenografts. These results strongly support the further characterization of the novel COBRA design in preclinical development studies. |
| Databáze: | OpenAIRE |
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