The Goldilocks Zone: Optimizing T Cell Engager Affinity, Kinetics and Architecture for Anti-Tumor Efficacy

Abstract

Cancer remains a leading cause of morbidity and mortality worldwide, despite marked progress in standard of care treatments like chemotherapy and radiotherapy. Such approaches have shown poor specificity, systemic toxicity and immunosuppression, prompting the development of immunotherapies to boost the immune system’s anti-tumor capacity. The ability of tumor cells to evade T cell immune surveillance has shifted the focus to T cell immunotherapies, which potentiate T cells to target and kill tumor cells. Despite the initial high promise of adoptive T cell therapies, clinical application has been hindered by low intratumoral infiltration and activity, systemic toxicities and high costs, stressing the need for more effective approaches. T cell engagers (TCEs) are a rapidly growing class of antibody-based drugs that integrate T cell-targeting moieties and tumor-associated antigen (TAA)-targeting moieties in a single molecule that bridges T cells with tumor cells. This leads to immunological synapse (IS) formation and T cell cytotoxicity. Although their modular architecture, higher tumor infiltration capacity and polyclonal T cell activation has been translated into clinical successes in various hematological malignancies, their poor efficacy in solid tumors, along with offtargeting and cytokine release syndrome (CRS) pose major challenges for wider use. In this review, a thorough investigation of how binding and kinetic parameters of TCEs could be optimized for effective TCE development has been compiled. This was achieved within the context of various factors influencing the binding properties of TCEs, such as their architecture, target epitope selection and expression, and IS characteristics. Based on the key insights of this assessment, a holistic approach example is presented, and considerations for future TCE development and clinical treatment are discussed.