Abstract
Invariant natural killer T-lymphocytes (iNKT) are a unique subset of immunomodulatory innate T-cells with an invariant TCRα chain recognizing glycolipids presented on the MHC class-I-like CD1d molecule. Activated iNKT rapidly secrete pro-and anti-inflammatory cytokines, potentiate innate and adaptive immunity, and modulate inflammation. While iNKT activation by glycolipid agonists are being explored as an adjuvant, their use depends on CD1d-restricted antigen presentation. Here, we report the effects of iNKT activation by a novel humanized monoclonal antibody, NKTT320, that binds to the invariant region of the iNKT TCR. A single dose of NKTT320 led to rapid iNKT activation, increased polyfunctionality, and elevation of multiple pro-inflammatory and chemotactic plasma analytes within 24 hours in cynomolgus macaques. Flow cytometry and RNA-Seq confirmed downstream effects of NKTT320 on multiple immune cell subsets. Inflammatory response, JAK/STAT and PI3K/AKT pathway genes were enriched along with upregulation of the inflammation-modulating genes CMKLR1, ARG2 and NLRP12. Finally, NKTT320 induced iNKT trafficking to adipose tissue and did not cause iNKT anergy. Our data indicate that NKTT320 has a sustained effect on in vivo iNKT activation, potentiation of innate and adaptive immunity, and resolution of inflammation, properties that support its future application as an immunotherapeutic and vaccine adjuvant.
Competing Interest Statement
Dr. Robert Schaub's former employment with NKT Therapeutics, the manufacturer of NKTT320, may be considered a potential conflict of interest. This is not a financial conflict of interest.
Footnotes
Conflict of interest statement: Dr. Robert Schaub’s former employment with NKT Therapeutics, the manufacturer of NKTT320, may be considered a potential conflict of interest.