2 Quantitation of CD137 and Nectin-4 expression across multiple tumor types to support indication selection for BT7480, a Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™)
| Autor: | Sebastien Hazard, Stephen J. Blakemore, Tara Gelb, Heather Cohen, Carly T. Campbell, Phil Brandish, Kristen Hurov, Dominic P. Smethurst, Erinn Parnell, David Galbraith, Mate Nagy, Qingyan Au, Nicholas Keen, Dan Rozelle, Johanna Lahdenranta |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Cancer Research Bladder cancer medicine.diagnostic_test medicine.drug_class Immunology Cell CD137 Neoplasms. Tumors. Oncology. Including cancer and carcinogens Biology Monoclonal antibody medicine.disease Immunofluorescence Immune system medicine.anatomical_structure Oncology Cancer cell Cancer research medicine Molecular Medicine Immunology and Allergy CD8 RC254-282 |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss Suppl 2 (2021) |
| ISSN: | 2051-1426 |
| Popis: | BackgroundBicycles are fully synthetic constrained peptides with antibody-like affinities that target selectively, readily penetrate tumor tissue, have relatively short half-lives, and can be chemically linked together to generate multifunctional molecules. BT7480 is a Bicycle TICA™ that binds both CD137 on immune cells and Nectin-4 on cancer cells to deliver a potent anti-tumor immune signal in Nectin-4 expressing tumors. Nectin-4 has been reported to be highly expressed in a wide range of human solid tumors, however the expression of CD137, abundance and localization of CD137+ immune cells in Nectin-4+ tumors are unknowns. A translational and informatics pipeline was established to interrogate the human tumor microenvironment to identify patient populations most likely to benefit from BT7480, which is being developed as a potential first-in-class molecule for the treatment of high unmet need cancers associated with Nectin-4 expression.MethodsTCGA RNAseq data for Nectin-4 and CD137 were analyzed from ~10,000 samples across 36 human cancers. Using a proprietary Nectin-4 mAb and MultiOmyx™ technology, a 19-plexed immunofluorescence assay was developed to simultaneously quantify the presence of Nectin-4+ and CD137+ cells, identify immune cell subsets and their spatial topography in 43 human tumor FFPE samples from HNSCC, lung, bladder, and breast cancers. Each FFPE slide was presented to a pathologist for tissue annotation and selection of regions of interest for image analysis. Proprietary deep learning-based workflows were applied to identify stroma and tumor regions, individual cells and perform cell classification for phenotypes of interest.ResultsRNA expression analysis indicated co-expression of Nectin-4 and CD137 in several tumor types with >50% tumors within NSCLC, HNSCC, breast, esophageal, and ovarian cancers expressing high levels of both targets. Spatial proteomic studies in HNSCC, lung, breast and bladder cancer samples demonstrated that Nectin-4 and CD137 co-expression at the protein level (>1% positive cells) was detected in 74% samples tested. CD137+ cells in Nectin-4+ tumors were identified as CD4+ T cells (37.6%), CD8+ T cells (16.8%) and CD68+ macrophages (5.9%). A subset of CD137+ cells (32.7%) were found to be deeply tumor penetrant and within close proximity of Nectin-4+ tumor cells across all indications tested.ConclusionsResults from this study support prioritization of indications for BT7480 clinical development and the utility of the MultiOmyx™ assay to monitor Nectin-4 and CD137 expression and to demonstrate proof-of-mechanism for the BT7480 FIH clinical trial expected to start in 2H-2021. |
| Databáze: | OpenAIRE |
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