TCR mimic T cell engagers targeting HLA/peptide complexes enable recognition of tumor-associated intracellular proteins, expanding the antigen space for cancer immunotherapy. Potency, specificity and developability are key attributes for the design of TCR mimic T cell engager. Integration of display technologies, pHLA-Fv structural insights, focused libraries, and innovative bispecific formats enable discovery and enhancement of pHLA-directed T cell engagers, offering a promising strategy for next-generation cancer therapeutics.

MAIT cells are an abundant, tissue and tumor resident, potent cytotoxic T cell subset. MAIT engagers (bispecific BiXAb antibodies) induce efficient tumor cytotoxicity but, in contrast to CD3 engagers, do not cause cytokine release. MAIT engagers do not induce regulatory T cell activation and are thus not dampened by increased immune suppression in the tumor. The increased safety and activity, especially in T-reg-rich tumors, affords a large therapeutic window.

This presentation will describe the development of a first-in-class T cell engager designed to target the T cell receptor β chain as a novel entry point for treating solid tumors. It will outline the overarching concept, general engineering strategy, and supporting preclinical observations.

T cell engagers (TCEs) can redirect immune cells to eliminate solid tumors, but their therapeutic index is limited by the scarcity of truly tumor-specific antigens that remain expressed under immune pressure. Neoantigens from driver mutations are both tumor-exclusive and essential for survival. Clasp’s TCEs targeting p53 and KRas neoantigens demonstrate high selectivity and potent anti-tumor activity in preclinical models, offering a precision approach to immunotherapy.

EM1042 is a first-in-class TCE targeting eosinophils for treating eosinophil-related chronic inflammatory and allergic diseases. In vitro, it depletes eosinophils more effectively than the benralizumab analog, with minimal CRS. In murine asthma models, its surrogate molecule reduced tissue eosinophil and IgE more than the parental mAb, due to depletion of specific B cell subsets. In a monkey asthma model, EM1042 induced significantly deeper eosinophil depletion than the benralizumab analog.

Ability Biotherapeutics developed AbiLeap, an AI-enabled platform that systematically designs conditionally active, logic-gated antibodies. Focusing on CD3 and select tumor antigens such as mesothelin, these molecules overcome key therapeutic limitations by activating only in the tumor microenvironment while remaining inert in normal tissue. We demonstrate how AbiLeap enables on-demand generation of large antibody sets meeting defined design criteria for the efficient creation of logic-gated immune engagers.

LabGenius Therapeutics’ platform leverages avidity-driven selectivity to overcome T cell engager (TCE) challenges, including on-target, off-tumor toxicity. We describe how the closed-loop integration of high-throughput experimentation with machine learning has facilitated the discovery and optimization of multispecifics for function and developability. We share in vitro data demonstrating selective tumor-cell killing, alongside in vivo data highlighting the efficacy and tolerability of our lead asset, a highly tumor-selective bispecific TCE.

Preclinical and clinical data support combinations of bispecific antibodies engaging distinct T cell signaling pathways. Co-localizing "signal 1" (TCR/CD3) and "signal 2" (costimulation) within the tumor microenvironment by combining CD3-engaging and costimulatory pathway-engaging bispecific antibodies drives superior anti-tumor responses. Integrating signal 3 (cytokine support) through targeted delivery of cytokine signaling also enables deeper and more durable anti-tumor responses.

Synaptimmune Therapeutics, in collaboration with Lyvgen Biopharma, is developing conditionally active costimulatory T cell engagers (TCE) for autoimmune diseases and solid tumors. Leveraging our proprietary conditionally active (hidden CD3 binder) and integrated costimulation TCE platform (TROY-Ig) we have developed more potent and safe conditionally active 4-1BB costimulatory CD19 x CD20 TCEs (SYN8034) for autoimmunity and conditionally active CD2 costimulatory DLL3 TCEs (SYN8463) for SLC solid-tumor clinical development.

Oncology has arguably the greatest potential to benefit from mRNA technology, as antibody-based immunotherapies, which can easily be encoded as mRNA, have revolutionized care for many cancer types. Despite recent advances, multiple myeloma (MM) remains a largely incurable malignancy where patients cycle through many therapies. We have developed dual targeting mRNA encoded T cell engagers for combination treatment of MM, to improve depth and durability of remission.