Abstract T-cell engagers (TCEs) have emerged as a transformative class of targeted immunotherapies, redirecting cytotoxic T cells toward malignant cells and reshaping the oncology treatment landscape. The CD19 BiTE® molecule blinatumomab pioneered this approach in hematologic malignancies, demonstrating that engineered bispecific proteins can induce deep and durable responses by harnessing endogenous T cells. Subsequent approvals across blood cancers have validated the modality. However, translating this success to solid tumors has proven considerably more complex. Solid tumors present distinct biological and clinical challenges, including intratumoral antigen heterogeneity, limited tumor-selective expression, immunosuppressive microenvironments, and safety risks driven by on-target, off-tumor activity. Cytokine-mediated toxicities and narrow therapeutic windows further constrain development. Addressing these barriers requires an integrated strategy spanning tumor biology, molecular engineering, and clinical design. In this presentation, we will highlight core principles guiding next-generation TCE development. Beyond rational target selection, advances in protein engineering are enabling precise control of immune activation. Affinity tuning of tumor and CD3 binding domains, optimization of epitope geometry to influence immune synapse formation, and avidity-driven formats such as asymmetric 2+1 architectures can preferentially direct activity toward high-density tumor cells while reducing effects on normal tissues. Dual-targeting, logic-gated designs introduce combinatorial specificity by requiring co-expression of two tumor antigens for optimal activation. Scaffold and half-life engineering further refine pharmacokinetics and cytokine kinetics to improve therapeutic index. By integrating structural biology, immunology, and clinical pharmacology, protein architecture becomes a deliberate lever for precision immunotherapy. These innovations position next-generation TCEs to expand T-cell redirection into solid tumors and redefine the future of targeted cancer immunotherapy. Citation Format: Angela Coxon. From molecular design to therapeutic impact: Protein engineering driving T-cell engager innovation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr PL05-03.
Angela Coxon (2026) studied this question.