| Autor: |
Chun JH, Lim BS, Roy S, Walsh MJ, Abhiraman GC, Zhangxu K, Atajanova T, Revach OY, Clark EC, Li P, Palin CA, Khanna A, Tower S, Kureshi R, Hoffman MT, Sharova T, Lawless A, Cohen S, Boland GM, Nguyen T, Peprah F, Tello JG, Liu SY, Kim CJ, Shin H, Quijano-Rubio A, Jude KM, Gerben S, Murray A, Heine P, DeWitt M, Ulge UY, Carter L, King NP, Silva DA, Kueh HY, Kalia V, Sarkar S, Jenkins RW, Garcia KC, Leonard WJ, Dougan M, Dougan SK, Baker D |
| Jazyk: |
angličtina |
| Zdroj: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Dec 07. Date of Electronic Publication: 2024 Dec 07. |
| DOI: |
10.1101/2024.12.06.626481 |
| Abstrakt: |
Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a broad range of affinities while dampening suppressive regulatory T (Treg) cell responses, but current approaches achieve these goals with limited success. Here, we report a de novo IL-21 mimic, 21h10, designed to have augmented stability and high signaling potency in both humans and mice. In multiple animal models and in ex vivo human melanoma patient derived organotypic tumor spheroids (PDOTS), 21h10 showed robust antitumor activity. 21h10 generates significantly prolonged STAT signaling in vivo compared with native IL-21, and has considerably stronger anti-tumor activity. Toxicities associated with systemic administration of 21h10 could be mitigated by TNFα blockade without compromising antitumor efficacy. In the tumor microenvironment, 21h10 induced highly cytotoxic antitumor T cells from clonotypes with a range of affinities for endogenous tumor antigens, robustly expanding low-affinity cytotoxic T cells and driving high expression of interferon-𝛾 (IFN-𝛾) and granzyme B compared to native IL-21, while increasing the frequency of IFN-𝛾 + Th1 cells and reducing that of Foxp3 + Tregs. As 21h10 has full human/mouse cross-reactivity, high stability and potency, and potentiates low-affinity antitumor responses, it has considerable translational potential. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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