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IGFBP7:免疫治療新靶點

來源:北京義翹神州科技股份有限公司   2024年10月18日 11:46  

  言

胰島素樣生長因子結(jié)合蛋白7(IGFBP7)是胰島素超家族的生長促進肽成員,可與胰島素和IGF結(jié)合,調(diào)控細(xì)胞生長和分化。IGFBP7在不同的腫瘤類型中表現(xiàn)出抑制或促進腫瘤生長的“自相矛盾”活性。研究發(fā)現(xiàn)IGFBP7可增強治療性單克隆抗體的抗腫瘤作用,并在某些癌癥血清中含量高,正在成為多種疾病診斷的生物標(biāo)志物。

01 IGFBP7的生理學(xué)和病理學(xué)意義

IGFBP7在多種組織中表達,包括大腦、肝臟、胰腺和骨骼肌。IGFBP7通過調(diào)節(jié)組織中IGF的生物利用度和其受體(INSR-A、INSR-B、IGF-1R、IGF-2R)的結(jié)合來發(fā)揮功能。通過與胰島素或IGF結(jié)合,激活下游三個重要的信號轉(zhuǎn)導(dǎo)通路:IRS-PI3K-AKT-mTOR、Ras-MEK-ERK和Ras-MAPK,誘導(dǎo)蛋白合成、細(xì)胞增殖、生長維持及抗凋亡。

 

IGFBP7在IGF依賴型或IGF獨立型癌癥類型中表達有所差異。在IGF獨立型癌癥中,IGFBP7可促進腫瘤細(xì)胞生長、血管生成、上皮間質(zhì)轉(zhuǎn)化(EMT)和細(xì)胞凋亡。IGFBP7還在多種類型的癌癥中呈現(xiàn)腫瘤抑制活性。通過與CD93結(jié)合,IGFBP7破壞腫瘤血管生成并增強免疫浸潤,進而增強CD93單克隆抗體的免疫治療效果。隨著研究的深入,IGFBP7正在成為各種疾病的生物標(biāo)志物,包括急性腎損傷、心衰和癌癥。

3-1.jpg

IGFBP7和癌癥相關(guān)的潛在機制和途徑。

(源自:doi.org/10.3389/fonc.2020.00727)

02 IGFBP7從實驗室到臨床應(yīng)用

IGFBP7在胃癌、前列腺癌、結(jié)直腸癌、膀胱癌和食道癌中表達上調(diào)。IGFBP7在腫瘤生成中的復(fù)雜生物學(xué)作用和分子機制仍然是臨床前關(guān)注的焦點。截至2023年8月,臨床研究主要集中在IGFBP7在急性腎損傷和心衰中的作用。

 

03 IGFBP7在研究中的應(yīng)用

IGFBP7蛋白和抗體用于研究腫瘤微環(huán)境和配受體相互作用機制。Sun團隊使用IGFBP7抗體(貨號:13100-R003,義翹神州)CD93抗體(貨號:12589-MM01,義翹神州)阻斷IGFBP7和CD93相互作用。通過免疫熒光染色檢測組織樣本中IGFBP7的表達情況。Yamamoto團隊利用重組IGFBP7蛋白(貨號:13100-H08H,義翹神州)研究LRP1的配體。

用于流式細(xì)胞術(shù)檢測

3-2.jpg

 

添加人源CD93單抗(貨號:12589-MM01,義翹神州)IGFBP7單抗(貨號:13100-R003,義翹神州)可顯著降低IGFBP7蛋白與CD93-HEK293T細(xì)胞的結(jié)合,研究認(rèn)定IGFBP7是CD93的配體。(對照組為野生型HEK 293T細(xì)胞(紅色),實驗組為轉(zhuǎn)染CD93的HEK293T細(xì)胞。源自:doi: 10.1126/scitranslmed.abc8922)

用于免疫熒光檢測

3-3.jpg

對來自正常組織的胰腺、皮膚和原位KPC、皮下植入B16的腫瘤樣本進行染色,結(jié)果發(fā)現(xiàn)IGFBP7在腫瘤脈管系統(tǒng)中表達上調(diào)。IGFBP7(綠色)和CD31(紅色)。(源自:doi: 10.1126/scitranslmed.abc8922)

用于LC-MS/MS質(zhì)譜檢測

3-4.jpg

 

評估了不同濃度下HMGB1(貨號:10326-H08H,義翹神州)、IGFBP7(貨號:13100-H08H,義翹神州)、SPARC(貨號:10929-H08H,義翹神州)、LIF(貨號:14890-H08H,義翹神州)等重組蛋白與LRP1之間的結(jié)合親和力,結(jié)果發(fā)現(xiàn)HMGB1(6.4nM)、IGFBP7(11nM)、SPARC(41nM)等親和力較高,LIF(>200nM)親和力較低。(源自:doi: 10.1016/j.matbio.2022.08.007)

 

?義翹神州IGFBP7明星產(chǎn)品

IGFBP7 Protein, Human, Recombinant (hFc & AVI Tag), Biotinylated, HPLC-verified, Cat: 13100-H41H-B

 

高純度:

3-5.png

 

Purity ≥ 90 % as determined by SDS-PAGE and SEC-HPLC

 

結(jié)合活性

3-6.png

 

Immobilized human CD93 protein can bind IGFBP7 protein. The EC50 is 7-21 ng/mL.

 

IGFBP7 Protein, Human, Recombinant (K95R, His Tag), HPLC-verified, Cat: 13100-H07H1

 

結(jié)合活性

3-7.png

Immobilized human IGFBP7 Protein can bind human CD93 protein with a linear range of 0.7-5.0 μg/mL.

更多IGFBP7明星產(chǎn)品

貨號

種屬

標(biāo)簽

純度

13100-H56H-B

 

Human

His & AVI

≥90%

13100-H02H

 

Human

hFc

85%

13100-H07H

 

Human

His

92%

13100-H08H

 

Human

His

92%

51125-M02H

 

Mouse

hFc

95%

SEC-HPLC

【參考文獻】

1. Qiaoyun Zhao, et al. Increased IGFBP7 Expression Correlates with Poor Prognosis and Immune Infiltration in Gastric Cancer. Journal of Cancer 2021. doi: 10.7150/jca.50370.

2. Yi X, et al. IGFBP7 and the Tumor Immune Landscape: A Novel Target for Immunotherapy in Bladder Cancer. Front. Immunol. 2022. doi: 10.3389/fimmu.2022.898493.

3. CD93 Blockade Stabilizes Tumor Vasculature to Improve Therapy Response. Cancer Discovery (2021) 11(10):2368. doi: 10.1158/2159-8290.Cd-rw2021-113.

4.  Huang X, et al. The Diagnostic Value of Serum IGFBP7 in Patients with Esophageal Squamous Cell Carcinoma. J Cancer 2019, 10(12):2687-2693.

5. Jin L, et al. Insulin Growth Factor Binding Protein 7 (IGFBP7)-Related Cancer and IGFBP3 and IGFBP7 Crosstalk. Frontiers in Oncology, 2020. doi.org/10.3389/fonc.2020.00727.

6. Yamanaka Y, et al. Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. J Biol Chem. 1997. doi: 10.1074/jbc.272.49.30729.

7. Oh Y., et al. Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I -II. J Biol Chem. 1996. doi: 10.1074/jbc.271.48.30322.

8. de Meyts P, et al. Insulin and IGF-I receptor structure and binding mechanism. In: Saltiel AR, Pessin JE, editors.Madame Curie Bioscience Database [Internet]. Austin, TX: Landes Bioscience (2000–2013). Available online at: ncbi.nlm.nih.gov/books/NBK6192/

9. Li Y, et al. Downregulated IGFBP7 facilitates liver metastasis by modulating epithelialmesenchymal transition in colon cancer. Oncol Rep 2019, 42(5):1935-1945.

10. Cai X, et al. Silence of IGFBP7 suppresses apoptosis and epithelial mesenchymal transformation of high glucose induced-podocytes. Exp Ther Med 2018, 16(2):1095-1102.

11. Sun Y, et al. Blockade of the CD93 Pathway Normalizes Tumor Vasculature to Facilitate Drug Delivery and Immunotherapy. Sci Trans Med, 2021. doi: 10.1126/scitranslmed.abc8922.

12. Gao, J.,et al. IGFBPrP1 affects the proliferation, apoptosis and macrophage polarization of endometrial cancer cells by regulating the PI3K/AKT pathway. Experimental and Therapeutic Medicine, 2023. doi.org/10.3892/etm.2023.11868.

13. Y. Xie, et al., Tissue inhibitor metalloproteinase-2 (TIMP-2) • IGF-binding protein-7 (IGFBP7) levels are associated with adverse outcomes in patients in the intensive care unit with acute kidney injury,ssss Kidney International, 2019, doi: 10.1016/j.kint.2019.01.020.

14. Zhang, L., et al. Insulin-like growth factor-binding protein-7 (IGFBP7) links senescence to heart failure. Nature Cardiovascular Research, 2022. doi.org/10.1038/s44161-022-00181-y.

15. Bolomsky, et al. Insulin like growth factor binding protein 7 (IGFBP7) expression is linked to poor prognosis but may protect from bone disease in multiple myeloma. BMC, 2015. doi.org/10.1186/s13045-014-0105-1.

16. Smith E, et al. IGFBP7 is associated with poor prognosis in oesophageal adenocarcinoma and is regulated by promoter DNA methylation. Br J Cancer, 2014. doi.org/10.1038/bjc.2013.783.

17. Qiu, B., et al. Diagnostic Value of Serum Insulin-Like Growth Factor Binding Protein 7 (IGFBP7) in Colorectal Cancer. OncoTargets and therapy, 2020. doi.org/10.7717/peerj.15419.

18. National Library of Medicine (U.S.). (n.d.). ClinicalTrials.gov. Retrieved July 14, 2023, from  clinicaltrials.gov/search?term=IGFBP7.

19. Sun, Y., et al. Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy. Science Translational Medicine,2021. doi.org/10.1126/scitranslmed.abc8922.

20. Yamamoto, K., et al. A top-down approach to uncover the hidden ligandome of low-density lipoprotein receptor-related protein 1 in cartilage. Matrix Biology, 2022. doi.org/10.1016/j.matbio.2022.08.007.


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