891 Pre-clinical development of a best-in-class bispecific T cell engager targeting a highly abundant peptide for the treatment of melanoma
Year: 2026
Type: conference-abstract
Abstract: Background Despite checkpoint inhibitor advances, approximately 40–50% of metastatic melanoma patients exhibit primary resistance to anti-PD-1/CTLA-4, with limited second-line options, resulting in 60,000 deaths from the disease globally each year. 1 TCR-based T cell engagers (TCR-TCEs) provide an alternative approach and have demonstrated a notable survival benefit in a subset of melanoma patients2; however, low target abundance may limit the overall clinical efficacy of current therapies. We therefore sought to identify a melanoma peptide-HLA target with exceptional abundance, tumor-restricted expression, and universal HLA-A*02 patient coverage. Using our novel TCR-TCE (T-SynapseTM) we then sought to develop a half-life extended TCE against this target.Methods Target copy number on primary tumor samples was quantified by fluorescent staining with a soluble, picomolar-affinity TCR. Tumor specificity of our lead T-Synapse-TCE was confirmed by functional screening using patient-derived material and cell lines derived from normal healthy tissues. Primary cell assays were used to measure tumor cell killing (live cell imaging) and T cell activation (IFN-y release). Finally, pharmacokinetics and inhibition of tumor growth were assessed using in vivo models.Results We identified a novel target, designated TC11, which has >25-fold higher copy number than the clinically-validated PRAME target and is expressed in >95% of uveal and cutaneous melanoma patients. A TCE targeting TC11, designated T-Synapse-TC11, was shown to drive tumor cell killing across all metastatic melanoma stages, sites, and treatment histories, therefore enabling patient enrolment without the need for biomarker selection. In vitro, T-Synapse-TC11 demonstrated robust activity, exceeding other clinical-stage TCR-TCEs, and importantly, was able to lyse cells obtained from checkpoint-resistant tumors, directly addressing primary and secondary resistance to anti-PD-1. The melanoma-restricted expression of TC11 was confirmed by the absence of off-target T cell activation in normal tissue panels. Patient-derived T cells, including exhausted effectors, low-frequency CD8+ donors, and cells from metastatic lesions were potently activated by T-Synapse-TC11 irrespective of prior anti-PD-1 exposure. In vivo, T-Synapse-TC11 reduced tumor burden and increased intratumoral T cell infiltration, with a PK supporting fortnightly dosing.Conclusions TC11 is a high copy number, melanoma-specific peptide target with broad patient coverage. T-Synapse-TC11 is a best-in-class TCR-TCE that demonstrates potent tumor cell lysis in vitro, in a checkpoint-resistant setting and with exhausted T cells. Pharmacokinetics support fortnightly dosing for durable tumor control. These attributes directly address the ~40–50% of metastatic melanoma patients who fail anti-PD-1 therapy without requiring biomarker stratification. IND submission is on track for H2 2027.References Global Cancer Observatory Melanoma of Skin [https://gco.iarc.who.int/media/globocan/factsheets/cancers/16-melanoma-of-skin-fact-sheet.pdf]Nathan P, Hassel J, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385:1196–206.Ethics Approval Work using human blood derived cells was approved by the South Central - Berkshire Research Ethics Committee; approval number 22/SC/0025 and the NHSBT; approval number NCI 2367. Commercial and collaborator supplied patient samples were supplied with informed consent and with certification from local research ethics committees
Authors: Samantha Drennan, Jong Fu Wong, Helena Horvatic, Laura Chaffey, Hemza Ghadbane, Dominic Hine, Peter Cain, Eleanor Bagg, Jana Rundle, Christos Gavriel, Sophie Wells, Samhita Rao, Mathew Veal, Michela Marongiu, Juan Bolivar, Xiaoyan Pan, Maria Busz, David Cook, Wilawan Bunjobpol, Alexander Stephens, Sophie Johnson, Oleksandr Dudchenko, Samuel Ward, Simon Wright, Amalia Martinez, Dzmitry Batrakou, Leonie Windeln, Thomas L Andresen, Joanne Oates, Mitchell P Levesque, Mark Lees, Graham Ogg, Nathaniel J Davies, Rebecca Ashfield, Sarah Leonard
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225158300