TCX-101, a trispecific T-cell engager (TcE) co-targeting a tumor-associated carbohydrate (TACA) antigen and a tumor-associated protein antigen (TAA) for the treatment of solid tumors with enhanced preclinical activity

Tumor-associated carbohydrate antigens (TACAs) are carbohydrate structures that result from aberrant glycosylation, a common feature of many cancers. Because TACA overexpression is associated with tumor progression, they represent attractive yet underexplored targets for cancer therapy.Tacalyx focuses on the generation of sophisticated antibodies against specific TACAs and successfully generated a high-affinity, humanized monoclonal antibody (mAb), TCX-101, targeting a TACA structure that is highly expressed across a broad range of cancer indications. Previously, our team demonstrated encouraging in vitro activity against breast and gastrointestinal (GI) cancers with TCX-101 as a bispecific T-cell engager (TcE) with a 2+1 CrossmAb format. To reduce off-tumor effects and enhance specificity, we explored a co-targeting approach by engineering a trispecific TcE comprising a CD3-engaging moiety and two tumor-targeting arms: one derived from the TCX-101 and another recognizing a tumor-associated protein antigen (TAA) overexpressed in epithelial tumors. This next-generation TcE demonstrated efficient in vitro cell binding and potent T-cell-mediated killing of cancer cells from multiple tumor indications expressing varying levels of the TACA and TAA, at very low effector-to-target ratios with human peripheral blood mononuclear cells (PBMCs), and in some models at picomolar concentrations. In vivo evaluation of this TcE format is currently investigated using cell-line derived xenograft models in humanized mice. In conclusion, these results highlight the feasibility of incorporating TCX-101 as a co-targeting arm in a TcE for solid tumors, enabling dual recognition of a TACA and a TAA. Preclinical studies provide proof-of-concept for this approach and support further investigation and development.