更新于：2024-11-01

IL-2R x NKG2D

更新于：2024-11-01

基本信息

关联

项与 IL-2R x NKG2D 相关的药物

OPL-0101

靶点

IL-2R x NKG2D

作用机制

IL-2R激动剂 [+1]

在研机构

Valo Health LLC初创企业

原研机构

Courier Therapeutics, Inc.初创企业

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 IL-2R x NKG2D 相关的临床结果

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100 项与 IL-2R x NKG2D 相关的转化医学

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0 项与 IL-2R x NKG2D 相关的专利（医药）

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项与 IL-2R x NKG2D 相关的文献（医药）

2021-07-01·The Journal of Immunology2区 · 医学

Retargeting IL-2 Signaling to NKG2D-Expressing Tumor-Infiltrating Leukocytes Improves Adoptive Transfer Immunotherapy

2区 · 医学

Article

作者: Shi, Lei ; Mahgoub, Bayan ; Paragas, Lea ; Westwick, John ; Slobin, Jacqueline ; Mei, Zhongcheng ; Guo, Yizhan ; Li, Dongge ; Hata, Atsushi ; Banerjee, Anirban ; Lazear, Eric ; Slingluff, Craig ; Krupnick, Alexander Sasha ; Manafi, Amir ; Li, Kang

AbstractEx vivo expansion followed by reinfusion of tumor-infiltrating leukocytes (TILs) has been used successfully for the treatment of multiple malignancies. Most protocols rely on the use of the cytokine IL-2 to expand TILs prior to reinfusion. In addition, TIL administration relies on systemic administration of IL-2 after reinfusion to support transferred cell survival. The use of IL-2, however, can be problematic because of its preferential expansion of regulatory T and myeloid cells as well as its systemic side effects. In this study, we describe the use of a novel IL-2 mutant retargeted to NKG2D rather than the high-affinity IL-2R for TIL-mediated immunotherapy in a murine model of malignant melanoma. We demonstrate that the NKG2D-retargeted IL-2 (called OMCPmutIL-2) preferentially expands TIL-resident CTLs, such as CD8+ T cells, NK cells, and γδT cells, whereas wild-type IL-2 provides a growth advantage for CD4+Foxp3+ T cells as well as myeloid cells. OMCPmutIL-2–expanded CTLs express higher levels of tumor-homing receptors, such as LFA-1, CD49a, and CXCR3, which correlate with TIL localization to the tumor bed after i.v. injection. Consistent with this, OMCPmutIL-2–expanded TILs provided superior tumor control compared with those expanded in wild-type IL-2. Our data demonstrate that adoptive transfer immunotherapy can be improved by rational retargeting of cytokine signaling to NKG2D-expressing CTLs rather than indiscriminate expansion of all TILs.

2010-07-29·Journal of Leukocyte Biology3区 · 医学

FK506 causes cellular and functional defects in human natural killer cells

3区 · 医学

Article

作者: Lee, Kyung-Mi ; Kang, Hyoung Jin ; Kim, Sung Tae ; Bluestone, Jeffrey A ; Kim, Eun-Ok ; Ahn, Hyo Seop ; Kim, Nayoung ; Kim, Tae-Jin

AbstractFK506-mediated NK cell defects are associated with impaired IL-2 receptor signaling and selective down-regulation of NK receptors.The role of NK cells in allogeneic HCT has been increasingly appreciated, particularly in the GVL effect. Although FK506 has been used widely to prevent GVHD, its action was considered to be primarily through activated T cells. In this study, we provide direct evidence for the first time that human NK cells are immediate targets of FK506. Our in vivo data from patients undergoing peripheral blood stem cell transplantation or BMT showed a reduced number of NK cells with down-regulated CD25 expression in their peripheral blood compartment. Likewise, FK506 caused profound inhibition of NK cell proliferation in vitro and suppressed NK cytotoxicity and cytokine secretion in response to IL-2. These defects were accompanied by impaired cell clustering and selective down-regulation of adhesion molecules, ICAM-1, CD2, CD49d, and CD58. Furthermore, FK506 specifically inhibited expression of NKG2D, CD48, and DNAM1 receptors without affecting that of 2B4, NKp30, NKp44, and NKp46. As a result, natural cytotoxicity against K562 tumor targets was impaired, while leaving redirected ADCC via 2B4 intact. Finally, FK506-treated NK cells showed impaired IL-2R signaling and inhibition of STAT3. Collectively, these signaling impairments and selective down-regulation of NK receptors by FK506 may underlie the proliferative and functional defects of NK cells. Thus, our data provide a new insight into the mechanism of immunosuppression by FK506, which should be considered to interpret the outcome of graft transplantation.

Frontiers in Immunology2区 · 医学

Five Layers of Receptor Signaling in Î³Î´ T-Cell Differentiation and Activation

2区 · 医学

ReviewOA

作者: Silva-Santos, Bruno ; Ribot, Julie C ; Ribeiro, Sérgio T

The contributions of γδ T-cells to immunity to infection or tumors critically depend on their activation and differentiation into effectors capable of secreting cytokines and killing infected or transformed cells. These processes are molecularly controlled by surface receptors that capture key extracellular cues and convey downstream intracellular signals that regulate γδ T-cell physiology. The understanding of how environmental signals are integrated by γδ T-cells is critical for their manipulation in clinical settings. Here, we discuss how different classes of surface receptors impact on human and murine γδ T-cell differentiation, activation, and expansion. In particular, we review the role of five receptor types: the T-cell receptor (TCR), costimulatory receptors, cytokine receptors, NK receptors, and inhibitory receptors. Some of the key players are the costimulatory receptors CD27 and CD28, which differentially impact on pro-inflammatory subsets of γδ T-cells; the cytokine receptors IL-2R, IL-7R, and IL-15R, which drive functional differentiation and expansion of γδ T-cells; the NK receptor NKG2D and its contribution to γδ T-cell cytotoxicity; and the inhibitory receptors PD-1 and BTLA that control γδ T-cell homeostasis. We discuss these and other receptors in the context of a five-step model of receptor signaling in γδ T-cell differentiation and activation, and discuss its implications for the manipulation of γδ T-cells in immunotherapy.