Discovery of a novel IL-15 based protein with improved developability and efficacy for cancer immunotherapy

Hu, Qiyue; Ye, Xin; Qu, Xiangdong; Cui, Dongbing; Zhang, Lei; Xu, Zhibin; Wan, Hong; Zhang, Lianshan; Tao, Weikang

doi:10.1038/s41598-018-25987-4

Cited by 33 publications

(20 citation statements)

References 27 publications

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“…IL-15 could directly promote the anti-tumor activity of NK cells against HCC cell lines and hepatoma cells directly extracted from liver cancer tissues in vitro. The activation characteristics of CD8 + /CD4 + T cells and NK cells induced by IL-15 made full use in studies of Hu et al [53] and a novel molecule (called P22339) based on IL-15 was ingeniously constructed through a rational structure-based design. This study found that it could significantly inhibit the growth and metastasis of tumor in the rodent model both in vitro and in vivo, and also could activate the T and NK cells of the cynomolgus monkey, which showed great potential for cancer immunotherapy.…”

Section: Interaction Between Nkg2d and Ligandsmentioning

confidence: 99%

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

Wang¹,

Li²,

Sun³

2020

Biomolecules

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Hepatocellular carcinoma is a common malignant tumor with high mortality. Its malignant proliferation, invasion, and metastasis are closely related to the cellular immune function of the patients. NKG2D is a key activated and type II membrane protein molecule expressed on the surface of almost all NK cells. The human NKG2D gene is 270 kb long, located at 12p12.3–p13.1, and contains 10 exons and 9 introns. The three-dimensional structure of the NKG2D monomeric protein contains two alpha-helices, two beta-lamellae, and four disulfide bonds, and its’ signal of activation is transmitted mainly by the adaptor protein (DAP). NKG2D ligands, including MICA, MICB, and ULBPs, can be widely expressed in hepatoma cells. After a combination of NKG2D and DAP10 in the form of homologous two polymers, the YxxM motif in the cytoplasm is phosphorylated and then signaling pathways are also gradually activated, such as PI3K, PLCγ2, JNK-cJunN, and others. Activated NK cells can enhance the sensitivity to hepatoma cells and specifically dissolve by releasing a variety of cytokines (TNF-α and IFN-γ), perforin, and high expression of FasL, CD16, and TRAIL. NK cells may specifically bind to the over-expressed MICA, MICB, and ULBPs of hepatocellular carcinoma cells through the surface activating receptor NKG2D, which can help to accurately identify hepatoma, play a critical role in anti-hepatoma via the pathway of cytotoxic effects, and obviously delay the poor progress of hepatocellular carcinoma.

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Section: Interaction Between Nkg2d and Ligandsmentioning

confidence: 99%

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

Wang¹,

Li²,

Sun³

2020

Biomolecules

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“…Although some encouraging clinical results were observed, the bioactivity of IL15 is limited due to short in vivo half-life. N-803, formerly ALT-803, composed of N72D IL15 mutant, sushi domain of IL15Rα, and Fc domain of human IgG1, has been demonstrated to have longer serum half-life and more potent stimulatory effect on NK cells and T-lymphocytes than that of WT hIL15 [ 15 , 16 ]. N-803 has been shown to boost antitumor response of anti-PD-L1 antibody in triple negative breast and colon cancers in vivo and its combination with anti-PD-1 monoclonal antibody, Nivolumab, has been verified in safety to treat refractory metastatic non-small cell lung cancer patients with observed tumor responses [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of Recombinant Human IL15 Protein Fused with Albumin Binding Domain on Anti-PD-L1 Immunotherapy Efficiency and Anti-Tumor Immunity in Colon Cancer and Melanoma

Hsu

Liu

Tsai

et al. 2021

Cancers

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Anti-PD-L1 antibody monotherapy shows limited efficacy in a significant proportion of the patients. A common explanation for the inefficacy is a lack of anti-tumor effector cells in the tumor microenvironment (TME). Recombinant human interleukin-15 (hIL15), a potent immune stimulant, has been investigated in clinical trial with encouraging results. However, hIL15 is constrained by the short half-life of hIL15 and a relatively unfavorable pharmacokinetics profile. We developed a recombinant fusion IL15 protein composed of human IL15 (hIL15) and albumin binding domain (hIL15-ABD) and explored the therapeutic efficacy and immune regulation of hIL-15, hIL15-ABD and/or combination with anti-PD-L1 on CT26 murine colon cancer (CC) and B16-F10 murine melanoma models. We demonstrated that hIL15-ABD has significant inhibitory effect on the CT26 and B16-F10 tumor growths as compared to hIL-15. hIL-15-ABD not only showed superior half-life and pharmacokinetics data than hIL-15, but also enhance anti-tumor efficacy of antibody against PD-L1 via suppressive effect on accumulation of Tregs and MDSCs and activation of NK and CD8+T cells. Immune suppressive factors including VEGF and IDO were also decreased by combination treatment. hIL15-ABD combined with anti-PD-L1 antibody increased the activity of anti-tumor effector cells involved in both innate and adaptive immunities, decreased the TME’s immunosuppressive cells, and showed greater anti-tumor effect than that of either monotherapy.

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“…In addition to IL2 and IFNa, many cytokines were also tested including type II IFNs, IL4, IL6, IL12, IL18, and IL21, FLT-3 ligand, and M-CSF. Pegylated IL10 and several forms of IL15 are currently in clinical trials (68). Although several of the cytokines produced low rates of objective responses, development as single agents has not yet proceeded beyond phase II (69,70).…”

Section: Other Immunotherapies For Metastatic Melanomamentioning

confidence: 99%

Immunotherapy of Melanoma: Facts and Hopes

Weiss

Wolchok

Sznol

2019

Clinical Cancer Research

216

152

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Melanoma is among the most sensitive of malignancies to immune modulation. Although multiple trials conducted over decades with vaccines, cytokines, and cell therapies demonstrated meaningful responses in a small subset of patients with metastatic disease, a true increase in overall survival (OS) within a randomized phase III trial was not observed until the development of anti-CTLA-4 (ipilimumab). Further improvements in OS for metastatic disease were observed with the anti-PD-1-based therapies (nivolumab, pembrolizumab) as single agents or combined with ipilimumab. A lower bound for expected 5-year survival for metastatic melanoma is currently approximately 35% and could be as high as 50% for the nivolumab/ ipilimumab combination among patients who would meet criteria for clinical trials. Moreover, a substantial fraction of long-term survivors will likely remain progression-free without continued treatment. The hope and major challenge for the future is to understand the immunobiology of tumors with primary or acquired resistance to anti-PD-1 or anti-PD-1/anti-CTLA-4 and to develop effective immune therapies tailored to individual patient subsets not achieving long-term clinical benefit. Additional goals include optimal integration of immune therapy with nonimmune therapies, the development and validation of predictive biomarkers in the metastatic setting, improved prognostic and predictive biomarkers for the adjuvant setting, understanding mechanisms of and decreasing toxicity, and optimizing the duration of therapy.

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Discovery of a novel IL-15 based protein with improved developability and efficacy for cancer immunotherapy

Cited by 33 publications

References 27 publications

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

Preclinical Evaluation of Recombinant Human IL15 Protein Fused with Albumin Binding Domain on Anti-PD-L1 Immunotherapy Efficiency and Anti-Tumor Immunity in Colon Cancer and Melanoma

Immunotherapy of Melanoma: Facts and Hopes

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