CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Therapeutic targeting of CD47 using a tri-specific NK cell engager to inhibit multiple myeloma.
Therapeutic targeting of CD47 using a tri-specific NK cell engager to inhibit multiple myeloma.
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多发性骨髓瘤（MM）是一种血液系统恶性肿瘤，由于对治疗产生耐药性，目前仍是一种不可治愈的疾病；因此，迫切需要新的有效治疗策略，尤其是针对对标准治疗无应答的患者。已有报道显示，MM中分化簇47（CD47）高表达，且与疾病进展相关。CD47通过与SIRP蛋白结合，抑制巨噬细胞的吞噬作用以及NK细胞活性，从而发挥肿瘤免疫逃逸机制的作用。
因此，阻断CD47信号通路已成为一种有前景的肿瘤免疫治疗策略。在本研究中，我们证实MM细胞具有高CD47表达。我们构建并表征了一种靶向CD47的三特异性杀伤衔接器，即TriKE-CD47，其同时靶向MM细胞上的CD47和NK细胞上的CD16。
此外，它还包含一个IL-15部分，以增强NK细胞增殖。TriKE-CD47处理促进了过表达CD16的NK细胞（N6细胞）的显著增殖。在200 ng TriKE-CD47存在下，将MM细胞与N6细胞、原代NK细胞和单核细胞来源的巨噬细胞共培养，显著提高了NK细胞毒性和巨噬细胞对MM细胞的吞噬活性。
值得注意的是，TriKE-CD47的疗效与靶细胞上CD47表达水平直接相关，这反映了TriKE-CD47对靶抗原的特异性。
此外，TriKE-CD47在MM异种移植小鼠模型中有效抑制了肿瘤生长。综上所述，这些发现有力支持TriKE-CD47可能成为MM患者的一种潜在治疗药物。
Multiple myeloma (MM), a hematological malignancy, remains an incurable disease due to the development of resistance to the treatment; thus, there is an urgent need for new and effective therapeutic strategies, particularly for patients who do not respond to standard therapies. High levels of Cluster of Differentiation 47 (CD47) expression have been reported in MM and are associated with disease progression. CD47 acts as a cancer immune escape mechanism by binding to SIRP protein, resulting in inhibiting phagocytosis of macrophages and NK cell activity.
Therefore, blocking the CD47 signaling pathway has emerged as a promising strategy for cancer immunotherapy. In this study, we confirmed that MM cells have high CD47 expression.
We generated and characterized a tri-specific killer engager targeting CD47, namely TriKE-CD47, that targets both CD47 on MM cells and CD16 on NK cells.
Additionally, it incorporates an IL-15 moiety to enhance NK cell proliferation. TriKE-CD47 treatment promoted a remarkable proliferation of NK cells overexpressing CD16 (N6 cells). Co-culturing MM cells with N6 cells, primary NK cells, and monocyte-derived macrophages in the presence of 200 ng of TriKE-CD47 significantly improved NK cytotoxicity and macrophage phagocyte activities against MM cells.
Notably, the efficacy of TriKE-CD47 was directly correlated with CD47 expression levels on the target cells reflecting the specificity of TriKE-CD47 to target antigen.
Furthermore, TriKE-CD47 effectively suppressed tumor growth in MM xenograft mice models. Taken together, these findings strongly supported that TriKE-CD47 could be a potential therapeutic for MM patients.
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