CD24 targeting bi-specific antibody that simultaneously stimulates NKG2D enhances the efficacy of cancer immunotherapy

Han, Yue; Sun, Fumou; Zhang, Xinrong; Wang, Tong; Jiang, Jiahao; Cai, Jialing; Gao, Qi; Hezam, Kamal; Liu, Yali; Xie, Jiajun; Wang, Min; Zhang, Juan

doi:10.1007/s00432-019-02865-8

Cited by 36 publications

(24 citation statements)

References 29 publications

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“…The data had demonstrated that the activated and expanded NK cells after genetic modification with NKG2D-CD3ζ-DAP10 could effectively kill HCC cells. Recently, Han et al [105] successfully constructed a novel antibody-ligand fusion rG7S-MICA (also known as bi-specific antibody, BsAb), which was composed of an anti-CD24 single-chain variable fragment (scFv) and extracellular domains of MICA. The rG7S-MICA had a high affinity with the antibody and could effectively enrich NK cells to the tumor-bearing site of liver cancer in nude mice, and could enhance the anti-tumor activity by promoting the release of IFN-γ and TNF-α from NK cells via the MICA-NKG2D/Fc-FcR pathway.…”

Section: Targeted Stimulation Of Nkg2d Improves the Therapeutic Effecmentioning

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: Targeted Stimulation Of Nkg2d Improves the Therapeutic Effecmentioning

confidence: 99%

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

Wang¹,

Li²,

Sun³

2020

Biomolecules

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“…Coupled with an abnormal upregulation of CD24 in multiple human carcinoma (68% and more specifically, 91% in ovarian carcinomas), has prompted its exploitation as a therapeutic biomarker [32À34]. Consequently, several reports have described therapeutic approaches including CAR [35], antibody conjugates [36,37], and bispecific antibodies [38] targeting CD24. Here we demonstrate the suitability of a CD24 antibody conjugate (CD24-AF750) for intraoperative FIGS in clinically relevant models of HGSOC, supporting its potential for translation in the intraoperative setting for ovarian cancer patients.…”

Section: Discussionmentioning

confidence: 99%

CD24-targeted intraoperative fluorescence image-guided surgery leads to improved cytoreduction of ovarian cancer in a preclinical orthotopic surgical model

et al. 2020

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Background: The completeness of resection is a key prognostic indicator in patients with ovarian cancer, and the application of tumour-targeted fluorescence image-guided surgery (FIGS) has led to improved detection of peritoneal metastases during cytoreductive surgery. CD24 is highly expressed in ovarian cancer and has been shown to be a suitable biomarker for tumour-targeted imaging. Methods: CD24 expression was investigated in cell lines and heterogenous patient-derived xenograft (PDX) tumour samples of high-grade serous ovarian carcinoma (HGSOC). After conjugation of the monoclonal antibody CD24 to the NIR dye Alexa Fluor 750 and the evaluation of the optimal pharmacological parameters (OV-90, n = 21), orthotopic HGSOC metastatic xenografts (OV-90, n = 16) underwent cytoreductive surgery with real-time feedback. The impact of intraoperative CD24-targeted fluorescence guidance was compared to white light and palpation alone, and the recurrence of disease was monitored post-operatively (OV-90, n = 12). CD24-AF750 was further evaluated in four clinically annotated orthotopic PDX models of metastatic HGSOC, to validate the translational potential for intraoperative guidance. Findings: CD24-targeted intraoperative NIR FIGS significantly (473%) improved tumour detection and resection, and reduced the post-operative tumour burden compared to standard white-light surgery in orthotopic HGSOC xenografts. CD24-AF750 allowed identification of minuscule tumour lesions which were undetectable with the naked eye in four HGSOC PDX. Interpretation: CD24-targeted FIGS has translational potential as an aid to improve debulking surgery of ovarian cancer.

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“…Different formats were used for therapy. These included unconjugated mAbs, where the effector mechanism mainly relies on antibody‐dependent cell‐mediated cytotoxicity of SWA11, 153,159 ALB9, 160 antibody‐drug conjugates, 161‐163 bispecific antibodies, 164 chimeric antigen receptor T cells 166 or chimeric antigen receptor‐natural killer cells 165 . In all these experiments more or less efficient killing of tumor target cells was observed in vitro or in vivo in human tumors grafted into immunodeficient mice.…”

Section: How Is Cd24 Expression Regulated?mentioning

confidence: 99%

Novel insights into the function of CD24: A driving force in cancer

Altevogt

Sammar

Hüser

et al. 2020

Intl Journal of Cancer

133

112

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CD24 is a highly glycosylated protein with a small protein core that is linked to the plasma membrane via a glycosyl‐phosphatidylinositol anchor. CD24 is primarily expressed by immune cells but is often overexpressed in human tumors. In cancer, CD24 is a regulator of cell migration, invasion and proliferation. Its expression is associated with poor prognosis and it is used as cancer stemness marker. Recently, CD24 on tumor cells was identified as a phagocytic inhibitor (“do not eat me” signal) having a suppressive role in tumor immunity via binding to Siglec‐10 on macrophages. This finding is reminiscent of the demonstration that soluble CD24‐Fc can dampen the immune system in autoimmune disease. In the present review, we summarize recent progress on the role of the CD24‐Siglec‐10 binding axis at the interface between tumor cells and the immune system, and the role of CD24 genetic polymorphisms in cancer. We describe the specific function of cytoplasmic CD24 and discuss the presence of CD24 on tumor‐released extracellular vesicles. Finally, we evaluate the potential of CD24‐based immunotherapy.

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CD24 targeting bi-specific antibody that simultaneously stimulates NKG2D enhances the efficacy of cancer immunotherapy

Cited by 36 publications

References 29 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

CD24-targeted intraoperative fluorescence image-guided surgery leads to improved cytoreduction of ovarian cancer in a preclinical orthotopic surgical model

Novel insights into the function of CD24: A driving force in cancer

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