TY - JOUR
T1 - A Humanized Mouse Model Coupled with Computational Analysis Identifies Potent Glycolipid Agonist of Invariant NKT Cells
AU - Saavedra-Avila, Noemi A.
AU - Pigni, Natalia B.
AU - Caldwell, Donald R.
AU - Chena-Becerra, Florencia
AU - Intano, Jose
AU - Ng, Tony W.
AU - Chennamadhavuni, Divya
AU - Porcelli, Steven A.
AU - Gascón, José A.
AU - Howell, Amy R.
N1 - Publisher Copyright:
© 2024 American Chemical Society
PY - 2023
Y1 - 2023
N2 - Invariant natural killer T (iNKT) cells play an important role in many innate and adaptive immune responses, with potential applications in cancer immunotherapy. The glycolipid KRN7000, an α-galactosylceramide, potently activates iNKT cells but has shown limited anticancer effects in human clinical trials conducted so far. In spite of almost three decades of structure-activity relationship studies, no alternative glycolipid has yet emerged as a superior clinical candidate. One reason for the slow progress in this area is that standard mouse models do not accurately reflect the specific ligand recognition by human iNKT cells and their requirements for activation. Here we evaluated a series of KRN7000 analogues using a recently developed humanized mouse model that expresses a human αTCR chain sequence and human CD1d. In this process, a more stimulatory, previously reported but largely overlooked glycolipid was identified, and its activity was probed and rationalized via molecular simulations.
AB - Invariant natural killer T (iNKT) cells play an important role in many innate and adaptive immune responses, with potential applications in cancer immunotherapy. The glycolipid KRN7000, an α-galactosylceramide, potently activates iNKT cells but has shown limited anticancer effects in human clinical trials conducted so far. In spite of almost three decades of structure-activity relationship studies, no alternative glycolipid has yet emerged as a superior clinical candidate. One reason for the slow progress in this area is that standard mouse models do not accurately reflect the specific ligand recognition by human iNKT cells and their requirements for activation. Here we evaluated a series of KRN7000 analogues using a recently developed humanized mouse model that expresses a human αTCR chain sequence and human CD1d. In this process, a more stimulatory, previously reported but largely overlooked glycolipid was identified, and its activity was probed and rationalized via molecular simulations.
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U2 - 10.1021/acschembio.3c00736
DO - 10.1021/acschembio.3c00736
M3 - Article
AN - SCOPUS:85187704794
SN - 1554-8929
JO - ACS Chemical Biology
JF - ACS Chemical Biology
ER -