CD47/SIRPα通路的替代药物

CD47/SIRPα通路是免疫治疗的重要通路，目前还没有专门的药物上市。因为CD47在红细胞、血小板等正常细胞上表达，原先一些CD47抗体药物临床试验中产生了重度贫血等严重的副作用。
" M1 M  A3 e& S2 h( iCD47/SIRPα通路有一些替代药物，这些药物，要么对CD47的结合不是那么强，要么是抑制SIRPα而不是CD47，因此避开了重度贫血等严重副作用。
一、Azelnidipine 阿折地平
. o+ _1 ^. {) H2 U9 _2 c《Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47/SIRPα and TIGIT/PVR Pathways for Cancer Immuno-Therapy》
Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8+ T cell in tumor and systematic immune response in the tumor-draining lymph node and spleen in a CD8+ T cell dependent manner. Our research suggests that the anti-hypertensive drug azelnidipine could be repositioned for cancer immunotherapy.
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二、氢气
《氢气通过调控CD47/CDC42通路抑制肺癌进展的研究》
1 b8 U3 N  @6 Q, X, V" ~1 K“结论:1.氢气处理能显著下调CD47的蛋白和m RNA的表达;2.氢气干预可明显抑制肺癌细胞增殖、转移和侵袭能力,并诱导细胞凋亡,增强巨噬细胞对肺癌细胞的吞噬作用;3.CD47敲除可协同氢气处理共同抑制肺癌细胞增殖、转移和侵袭能力,并诱导细胞凋亡;4.CD47过表达可显著削弱氢气的抗肿瘤作用;5.氢气干预同顺铂治疗效果一致,均可明显缓解肿瘤组织细胞异质。 ”
2 Q6 o& O& D5 `" L8 t2 Z' i7 [4 {吸氢气会降低血小板，跟这个研究也是相互验证的。
8 [4 N* s& D' n3 ^  c1 ?! I我在《给免疫治疗“减毒增效”的辅助药物（十二）--吸氢气或者补充辅酶Q10》文里讲了日本做的吸氢气联合o药显著改善o药疗效的临床试验，氢气抑制CD47应该也是一个可能得解释。

! W& ]3 Y" R' m/ F三、咳喘宁
# G  P2 _/ |7 ?4 j$ C1、《咳喘宁口服液干预SIRPα对RSV诱发哮喘大鼠模型NGF的影响》
结论:1.SIRPα及其配体CD 47参与哮喘的发作,咳喘宁口服液对其有调控作用,中剂量组效果最优。
2、《咳喘宁口服液干预哮喘模型大鼠SIRPα对Th1/Th2的调节作用》
结论1)哮喘发病时SIRPα及配体CD47表达明显增高,咳喘宁口服液能抑制SIRPα及配体CD47的表达,中剂量组效果最佳。
! D8 o6 J" o) N! `/ d7 g% a! J7 H咳喘宁口服液由炙麻黄、苦杏仁、桃仁、大青叶、黄芪、生石膏、细茶、甘草等多味中药组成，每瓶 100ml，含生药 70g，由湖南中医药大学第一附属医院药剂科制备。按临床量效关系观察结果拟定咳喘宁口服液高剂量 1ml/100g，中剂量 0.3ml/100g，低剂量 0.033ml/100g，生产批号 201610。
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四、维生素E琥珀脂酸
' _3 ?. Q0 W  X* a/ h$ Y《Vitamin E succinate exerts anti-tumour effects on human cervical cancer cells via the CD47-SIRPɑ pathway both in vivo and in vitro》
0 d( ], I- X! F6 bVitamin E succinate (RRR-a-tocopheryl succinate, VES) acts as a potent agent for cancer therapy and has no toxic and side effects on normal tissue cells. However, the mechanism by which VES mediates the effects are not yet fully understood. Here, we hypothesised that VES mediates antitumour activity on human cervical cancer cells via the CD47-SIRPɑ pathway in vivo and in vitro. Results indicated that the human cervical cancer HeLa cells treated with VES were more efficiently engulfed by THP-1-derived macrophages. In response to VES, the protein expression of CD47 on cell membranes and the mRNA level of CD47 in different human cervical cancer cells significantly decreased. And the level of calreticulin (CRT) mRNA in the VES-treated cells increased. By contrast, CRT protein expression was not altered. miRNA-155, miRNA-133 and miRNA-326 were up-regulated in the VES-treated HeLa cells. Knocking down miRNA-155 and miRNA-133 by RNA interference increased CD47 protein expression in the VES-treated cells. In vivo efficacy was determined in BALB/C nude mice with HeLa xenografts. Results showed that VES reduced tumour growth, increased overall survival and inhibited CD47 in the tumour transcriptionally and translationally. Furthermore, inflammatory factors (TNF-α, IL-12, IFN-γ, IL-2 and IL-10) in the spleen were altered because of VES treatment. Our results suggest that VES-induced antitumour activity is coupled to the CD47-SIRPɑ pathway in human cervical HeLa cancer cells.
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五、木犀草素
) V# g+ }1 F% G( s《Luteolin promotes macrophage-mediated phagocytosis by inhibiting CD47 pyroglutamation》
" D# y; b8 {# I2 D'Don't eat me' signal of CD47 is activated via its interaction with SIRPα protein on myeloid cells, especially phagocytic cells, and prevents malignant cells from anti-tumor immunity in which pyroglutamate modification of CD47 by glutaminyl-peptide cyclotransferase-like protein (isoQC) takes an important part evidenced by our previous report that isoQC is an essential regulator for CD47-SIRPα axis with a strong inhibition on macrophage-mediated phagoctyosis. Therefore, we screened for potential isoQC inhibitors by fluorescence-activated cell sorting assay and identified luteolin as a potent compound that blocked the pyroglutamation of CD47 by isoQC. We further demonstrated that luteolin directly bound to isoQC using pull-down assay and isothermal calorimetric (ITC) assay. In consistency, we showed that luteolin markedly abrogated the cell-surface interaction between CD47 and SIRPα in multiple myeloma H929 cells and consequently promoted the macrophage-mediated phagocytosis. Collectively, our study discovered a promising lead compound targeting isoQC, luteolin, which functions distinctly from current CD47 antibody-based drugs and therefore may potentially overcome the clinical side effects associated with CD47 antibody treatment-induced anemia.