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Background EVOLVE trispecific T cell engagers (TCEs) bind a tumor antigen and both CD3 and CD2 on T cells, thereby providing integrated CD2 costimulation ( figure 1). EVOLVE TCEs demonstrate superior T cell activation and tumor cell killing compared to traditional bispecific CD3 TCEs, without excess cytokine release or tonic T cell activation. EVOLVE TCEs may offer clinical benefits due to superior effector T cell activity and reduced T cell exhaustion.UL16 binding proteins 2, 5 and 6 (ULBP2/5/6) belong to a family of cell surface proteins whose endogenous ligand is the NKG2D protein. We have previously reported that cell-surface ULBP2/5/6 is not present in vital organs and found at low levels on nonkeratinizing, glycogenated epithelia. ULBP2/5/6 expression is significantly upregulated in transitional cell carcinomas of the urinary tract and squamous cell carcinomas of the lung, head and neck, esophagus, skin, and anogenital regions. With high cell-surface expression on cancer cells and limited expression in normal tissues, ULBP2/5/6 represents an intriguing target for cancer immunotherapy.EVOLVE104 is a trispecific TCE that binds ULBP2/5/6. In preclinical models, it outperforms matched bispecific CD3 TCEs with no evidence of target-independent T cell activation. No safety concerns were identified in preclinical toxicity studies, and the anticipated human half-life of EVOLVE104 is 12 days when administered intravenously.Methods EIU-104101 is a first-in-human phase 1a/1b study evaluating the safety, efficacy, pharmacokinetics and pharmacodynamics of EVOLVE104 in subjects with locally advanced or metastatic solid tumors, relapsed from or refractory to current standard of care. The study population will include subjects with urothelial carcinoma and squamous cell carcinomas of the lung, esophagus, skin, anus, cervix, and penis. The phase 1a portion of the study will enroll up to 80 subjects in a Bayesian optimal interval (BOIN) dose-escalation scheme with backfill available at dose levels deemed safe, with a key objective to identify one or more recommended doses for expansion (RDEs). Phase 1b consists of two expansion cohorts: Cohort A, which will be a dose optimization cohort in a single indication (to be determined based on the phase 1a observations) in which 40 subjects will be randomized 1:1 to two doses to determine the recommended phase 2 dose; and Cohort B, which will enroll up to 40 subjects in relevant indications other than the indication enrolling in Cohort A at one or more RDEs.Results Enrollment begins September 2026.Conclusions EVOLVE104 represents a promising new TCE modality targeting a novel tumor antigen.Trial Registration Listing on clinicaltrials.gov is pending.Ethics Approval Study EIU-104101 is currently under review by FDA and will only begin enrollment upon clearance from relevant health authorities and Institutional Review Boards/Independent Ethics Committees.Abstract 534 Figure 1EVOLVE104 is a trispecific T cell engager providing integrated costimulation via CD3 and CD2 binding and targeting the novel tumor antigen ULBP2/5/6