High‐Affinity Superantigen‐Based Trifunctional Immune Cell Engager Synergizes NK and T Cell Activation for Tumor Suppression

• Published in: Advanced science Vol. 11; no. 33; pp. e2310204 - n/a
• Main Authors: Yu, Yao‐An, Lien, Wan‐Ju, Lin, Wen‐Ching, Pan, Yi‐Chung, Huang, Sin‐Wei, Mou, Chung‐Yuan, Hu, Che‐Ming Jack, Mou, Kurt Yun
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.09.2024; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Antibodies; Antigens; cancer Immunotherapy; Cell Line, Tumor; CRISPR; Cytokines; Design; directed evolution; Disease Models, Animal; Evolution; fusion protein; Humans; immune cell engager; Immunotherapy - methods; Killer Cells, Natural - immunology; Libraries; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Mice; Mutation; Neoplasms - immunology; Neoplasms - therapy; Proteins; superantigens; Superantigens - immunology; T cell receptors; T-Lymphocytes - immunology; Tumors; Yeast; fusion protein; cancer Immunotherapy; immune cell engager; superantigens; directed evolution
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202310204

The development of immune cell engagers (ICEs) can be limited by logistical and functional restrictions associated with fusion protein designs, thus limiting immune cell recruitment to solid tumors. Herein, a high affinity superantigen‐based multivalent ICE is developed for simultaneous activation and recruitment of NK and T cells for tumor treatment. Yeast library‐based directed evolution is adopted to identify superantigen variants possessing enhanced binding affinity to immunoreceptors expressed on human T cells and NK cells. High‐affinity superantigens exhibiting improved immune‐stimulatory activities are then incorporated into a superantigen‐based tri‐functional yeast‐display‐enhanced multivalent immune cell engager (STYMIE), which is functionalized with a nanobody, a Neo‐2/15 cytokine, and an Fc domain for tumor targeting, immune stimulation, and prolonged circulation, respectively. Intravenous administration of STYMIE enhances NK and T cell recruitment into solid tumors, leading to enhanced inhibition in multiple tumor models. The study offers design principles for multifunctional ICEs. The Superantigen‐based Trifunctional Yeast‐display‐enhanced Multivalent Immune Cell Engager (STYMIE) integrates an engineered superantigen with enhanced immune stimulatory properties, a tumor‐targeted nanobody, an immune cell‐stimulating cytokine for prolonged immune cell survival, and an Fc domain for extended circulation. STYMIE successfully recruits NK and T cells to solid tumors, leading to substantial inhibition of tumor growth in various murine tumor models.