Cancer Immunotherapeutic Potential of NKTT320, a Novel, Invariant, Natural Killer T Cell-Activating, Humanized Monoclonal Antibody

• Published in: International journal of molecular sciences Vol. 21; no. 12; p. 4317
• Main Authors: Patel, Nishant P, Guan, Peng, Bahal, Devika, Hashem, Tanwir, Scheuplein, Felix, Schaub, Robert, Nichols, Kim E, Das, Rupali
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.06.2020; MDPI
• Subjects: Antibodies; Antibodies, Monoclonal, Humanized - pharmacology; Antigen presentation; Antigens; Antitumor activity; antitumor immunity; Biomarkers; Cancer; Cancer immunotherapy; CD1d antigen; CD25 antigen; CD69 antigen; Cell activation; Cell Degranulation - drug effects; Cell Degranulation - immunology; Cell growth; Cell Line, Tumor; Cell surface; Cytokines; Cytokines - metabolism; Cytotoxicity; Degranulation; Dendritic cells; Dilution; Dose-Response Relationship, Drug; Flow cytometry; Granzyme B; Histocompatibility Antigens Class II - immunology; Humans; Immune system; Immunophenotyping; Immunotherapy; Intracellular levels; invariant natural killer T cells; Invariants; Ligands; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes B; Lymphocytes T; Monoclonal antibodies; monoclonal antibody; Natural killer cells; Natural Killer T-Cells - drug effects; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; NKTT320; Software; T cell receptors; Therapeutic applications; Transformed cells; Tumor cells; Tumor necrosis factor-TNF; Tumors; United States > US; Grand Island New York; invariant natural killer T cells; NKTT320; monoclonal antibody; antitumor immunity; immunotherapy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21124317

Invariant natural killer T cells (iNKTs) directly kill tumor cells and trans-activate the anti-tumor functions of dendritic cells (DC), natural killer (NK) cells, and T and B cells. As such, iNKTs serve as a powerful tool for use in cell-based cancer immunotherapy. iNKT cell activation commonly requires engagement of the invariant T cell receptor (iTCR) by CD1d presenting glycolipid antigens. However, transformed cells often down-regulate CD1d expression, which results in a reduction of iNKT cell anti-tumor functions. One approach to circumvent this critical barrier to iNKT cell activation is to develop an agonistic antibody that binds directly to the iTCR without the requirement for CD1d-mediated antigen presentation. To this end, we have characterized the iNKT cell stimulatory properties of NKTT320, a novel, recombinant, humanized, monoclonal antibody that binds selectively and with high affinity to human iTCRs. Strikingly, immobilized NKTT320 mediated robust iNKT cell activation (upregulation of CD25 and CD69) and proliferation (carboxyfluorescein succinimidyl ester (CFSE) dilution), as well as Th1 and Th2 cytokine production. Additionally, iNKTs stimulated by plate-bound NKTT320 exhibited increased intracellular levels of granzyme B and degranulation (exposure of CD107 on the cell surface). Furthermore, both soluble and immobilized NKTT320 induced iNKT cell-mediated activation of bystander immune cells, suggesting that this novel anti-iTCR antibody facilitates both direct and indirect iNKT cell cytotoxicity. These studies are significant, as they provide a framework by which iNKT cell anti-cancer functions could be enhanced for therapeutic purposes.