T Cell Engagers

BiTAC-TCE employs dual-targeting and on-cell assembly of a split CD3 binder, enabling selective activation on dual antigen–positive tumour cells. Targeting EpCAM and a distinct antigen drives tumour-selective activity, demonstrating discrimination between tumour and healthy surrogate cells in 2D- and 3D-cell cultures and strong in vivo efficacy. A transgenic mouse model revealed no signs of toxicity, indicating a broader therapeutic index with the potential to overcome on-target, off-tumour toxicities.

Vir Biotechnology’s PRO-XTEN dual-masked T cell engagers (TCEs) are designed to remain inactive  until they reach the tumour microenvironment in order to spare healthy tissues. Once the masked TCE reaches the tumour microenvironment, the heightened protease activity releases the masks, unleashing the potent TCE core. This masking technology simultaneously provides extended half-life in circulation, masking of TCE activity, and improved manufacturability. PRO-XTEN dual-masked TCEs are currently being evaluated across three different tumour-associated antigens in clinical trials.

Conventional T cell engagers are constrained by on-target, off-tumour toxicity due to limited tumour-specific antigens. Plectonic’s logic-gated, multispecific T cell engagers (Logibodies) integrate dual-antigen recognition to achieve conditional T cell activation. This architecture drives potent and durable tumour cell killing in vitro and in vivo while minimising off-tumour toxicity. Plectonic advances a proprietary Logibody pipeline and welcomes collaborations to co-develop safe and effective, next-generation T cell therapies.

Ovarian cancer remains a leading cause of cancer mortality due to late diagnosis, frequent relapse, and limited benefit from current immunotherapies driven by the lack of tumour-specific antigens. Using Molecular Partners’ Switch-DARPin platform, we developed MP0632, a logic-gated CD3 T cell [MJ1] engager with CD2 co-stimulation, designed for ovarian cancer and extendable to additional solid tumours. It enables tumour-localised and conditional activation upon simultaneous recognition of mesothelin and EpCAM, driving potent and sustained antitumor activity, while minimising off-tumour toxicity.

The full potential of solid tumour targeting T cell bispecifics (TCB) is hampered by limited tumour penetration, T cell exhaustion and restricted tolerability for TCB targets with off-tumour expression. Co-dosing a T cell bispecific (TCB) with an excess of a fully Fc-functional competing antibody (AB) solves these challenges through improving tumour penetration, synergistic tumour cell killing, and critically, blocking off-tumour T cell activation thereby improving tolerability. TCAB demonstrates superior functionality across a range of targets, including 134TCAB targeting Fucosyl-GM1 in SCLC.

L19-TNF is a tumour-targeting TNF fusion protein directed against the extra-domain B of fibronectin that promotes vascular activation and immune infiltration. We evaluated L19-TNF in combination with a CEAxCD3 T cell engager to overcome the immune-excluded microenvironment of solid tumours. In colorectal cancer models, the combination enhanced T cell infiltration and TCE extravasation. The dual-modality approach improved anti-tumour activity and induced durable complete responses. Re-challenged animals showed immune memory, supporting a strategy to turn cold tumours hot.

T cell engagers (TCEs) have shown promising clinical efficacy, but are still associated with significant toxicities, such as cytokine release syndrome (CRS). To address this, we have developed novel affinity attenuated and CD8-biased TCEs. Case studies will be presented on the discovery and engineering of clinical lead candidates for CLDN18.2, CD20 and GPC-3, focusing the presentation on how the binders were generated and how the TCEs engage their receptors.

LGTX-101, a next-generation, ML-derived, selectivity-enhanced Nectin-4 x CD3 T-cell engager identified via the EVA platform, which screened >270,000 designs. Its novel 3+1 architecture drives targeted T-cell cytotoxicity with >78,000-fold selectivity for tumours over healthy cells. In humanised BT-474 xenograft models, LGTX-101 shows robust efficacy, achieving up to 98% tumour growth inhibition, including at low doses, supporting a promising therapeutic window for Nectin-4–expressing cancers. LGTX-101 is in IND enabling studies with a clinical trial anticipated to commence in H1 2027.