This presentation will review how combination of potency attenuation and masking increases preferential activity of cytokines on target cell populations; demonstrate activation of conditional cytokine by the combination of cis-engagement and tumor-derived products enriched in the TME; and show that combined strategies of masking, potency attenuation and tumor targeting can be incorporated to widen the therapeutic index.

The safety and efficacy of T cell engagers for solid tumour therapy is limited by the availability of tumour-specific antigens that share expression in defined patient populations. To address this, we discovered and validated DARKFOX, an alternative-ORF of FOXM1, which is expressed with high-prevalence, tumour specificity, and homogeneity in major tumour types. A peptide derived from DARKFOX is robustly presented by HLA-A3 (DARKFOX-A3), to which we have developed highly specific, pM-affinity TCR-mimic antibodies. When engineered in our EnTiCE T cell engager platform, ENA101 achieves robust in vitro and in vivo efficacy alongside a strong CMC profile. IND-enabling studies are in progress.

Autoimmune-mediated connective tissue diseases have a high unmet medical need as they remain diseases with high morbidity and mortality. Here, we review recent experiences on the treatment of severe, previously refractory patients with systemic autoimmune rheumatic disease with T Cell Engagers (TCEs) targeting different B-cell antigens (CD19, CD20, and BCMA) in compassionate use programmes and provide an update on ongoing and planned clinical trials.

Complex antibody formats, such as CrossMab and KiH, enable innovative Fab arrangements like 2+1 and 2+2 configurations, yet their impact on pharmacokinetics remains underexplored. By comparing 16 distinct, rationally designed formats, we identified significant differences in nonspecific clearance. Mechanistic studies revealed that these variations are primarily driven by format-dependent FcRn-mediated recycling efficiency, rather than cellular uptake. Notably, C-terminal Fab positioning improves recycling by reducing steric hindrance compared to N-terminal designs. These Fv-independent properties provide a robust framework to optimise therapeutic half-life through structural engineering, ensuring more predictable pharmacokinetic profiles during the development of next-generation antibody therapies.

The development of next‑generation antibody-based therapeutics requires human-relevant platforms capable of capturing the complexity of tumor–immune and tumor–stroma interactions. Here, we combine advanced 3D microencapsulated tumor microenvironment (TME) models to evaluate both cytotoxic and immunomodulatory antibody modalities. Using heterotypic breast cancer spheroids incorporating stromal fibroblasts, monocytes, and NK cells, we demonstrate that antibody–drug conjugates (ADCs) preserve target specificity and elicit robust, HER2‑dependent cytotoxicity, with stromal components modulating the magnitude of response. Complementary immune‑competent 3D models reveal that dual HER2 blockade enhances NK‑cell activation, accelerates tumor apoptosis, and reduces immunosuppressive PD‑L1⁺ myeloid populations, recapitulating clinically observed immune mechanisms of action. Together, these human 3D TME platforms provide a powerful testbed to de-risk antibody-based strategies, illuminate safety and efficacy determinants, and support the development of next‑generation bispecific, multispecific, and immunomodulatory therapeutic antibodies.