CD47-SIRPα-targeted therapeutics: status and prospects.
CD47-SIRPα-targeted therapeutics: status and prospects.
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DOI：
10.1016/j.iotech.2022.100070
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Weissman, I L
中科院分区：
文献类型：
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作者：
Maute, R;Xu, J;Weissman, I L
CD47是向吞噬细胞发出的一种“别吃我”信号，在许多肿瘤细胞上过表达，这是肿瘤逃避免疫监视的一种潜在机制。因此，CD47及其与吞噬细胞上信号调节蛋白α（SIRPα）的相互作用是一个很有前景的癌症治疗靶点。阻断CD47或SIRPα的治疗性抗体和融合蛋白已研发出来，并在血液肿瘤和实体瘤的临床前模型中显示出活性。贫血是抗CD47治疗常见的不良事件，但缓解策略（包括使用低“起始”剂量）在临床研究中已大幅降低了这种风险。虽然单药临床研究缺乏疗效，但CD47 - SIRPα阻断剂与增加“吃我”信号的药物或抗肿瘤抗体联合使用的研究结果很有前景。抗CD47抗体马格利单抗在该类药物的临床开发中进展最为领先。在Ib/II期研究中，马格利单抗联合疗法耐受性良好，在血液系统恶性肿瘤和实体瘤中显示出令人鼓舞的缓解率。其他抗CD47 - SIRPα药物的类似联合疗法研究也开始有相关报道。基于这些早期临床成果，针对血液肿瘤和实体瘤，许多测试CD47 - SIRPα阻断剂与标准疗法联合使用的试验已经启动。这些研究结果将有助于确定这种新方法在临床实践中的作用，人们正热切期待着。
CD47是在癌细胞上过表达的“别吃我”信号。
阻断CD47 - SIRPα信号通路可导致肿瘤细胞被吞噬。
CD47 - SIRPα阻断剂联合标准治疗显示出有前景的临床疗效。
在临床上，CD47 - SIRPα阻断剂联合标准治疗耐受性良好。
针对血液肿瘤和实体瘤的CD47 - SIRPα靶向临床试验正在进行中。
CD47 is a “don’t eat me” signal to phagocytes that is overexpressed on many tumor cells as a potential mechanism for immune surveillance evasion. CD47 and its interaction with signal-regulating protein alpha (SIRPα) on phagocytes is therefore a promising cancer target. Therapeutic antibodies and fusion proteins that block CD47 or SIRPα have been developed and have shown activity in preclinical models of hematologic and solid tumors. Anemia is a common adverse event associated with anti-CD47 treatment, but mitigation strategies—including use of a low ‘priming’ dose—have substantially reduced this risk in clinical studies. While efficacy in single-agent clinical studies is lacking, findings from studies of CD47–SIRPα blockade in combination with agents that increase ‘eat me’ signals or with antitumor antibodies are promising. Magrolimab, an anti-CD47 antibody, is the furthest along in clinical development among agents in this class. Magrolimab combination therapy in phase Ib/II studies has been well tolerated with encouraging response rates in hematologic and solid malignancies. Similar combination therapy studies with other anti-CD47–SIRPα agents are beginning to report. Based on these early clinical successes, many trials have been initiated in hematologic and solid tumors testing combinations of CD47–SIRPα blockade with standard therapies. The results of these studies will help determine the role of this novel approach in clinical practice and are eagerly awaited. CD47 is a “don’t eat me” signal overexpressed on cancer cells. Blockade of the CD47–SIRPα signaling pathway leads to phagocytosis of tumor cells. CD47–SIRPα blockade plus standard treatment shows promising clinical efficacy. Clinically, CD47–SIRPα blockade plus standard treatment is well tolerated. Clinical trials targeting CD47–SIRPα in hematologic and solid tumors are ongoing.