Targeted glycan degradation potentiates the anticancer immune response in vivo.
Targeted glycan degradation potentiates the anticancer immune response in vivo.
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DOI：
10.1038/s41589-020-0622-x
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发表时间：
2020-12
影响因子：
14.8
通讯作者：
Bertozzi CR
中科院分区：
文献类型：
--
作者：
Gray MA;Stanczak MA;Mantuano NR;Xiao H;Pijnenborg JFA;Malaker SA;Miller CL;Weidenbacher PA;Tanzo JT;Ahn G;Woods EC;Läubli H;Bertozzi CR
目前批准的靶向PD-1和CTLA-4受体通路的免疫检查点抑制剂疗法是某些癌症的强大治疗选择;然而，大多数癌症类型的患者仍然没有反应。因此，人们对发现和阻断介导免疫抑制的替代途径感兴趣。一种这样的机制是恶性肿瘤中唾液酸聚糖的上调，其最近已显示通过多种机制抑制免疫细胞活化，因此代表可靶向的糖免疫检查点。由于这些聚糖不是典型的药物，我们设计了一种α HER 2抗体-唾液酸酶偶联物，可以有效地选择性地从乳腺癌细胞中剥离不同的唾液酸聚糖。在同基因乳腺癌模型中，去唾液酸化增强了免疫细胞浸润和活化，并延长了小鼠的存活时间，这一效应依赖于在肿瘤浸润性骨髓细胞上发现的Siglec-E检查点受体的表达。因此，抗体-唾液酸酶缀合物代表了用于糖免疫检查点疗法的有前景的模式。
Currently approved immune checkpoint inhibitor therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, most patients across cancer types still fail to respond. Consequently, there is interest in discovering and blocking alternative pathways that mediate immune suppression. One such mechanism is an upregulation of sialoglycans in malignancy, which has been recently shown to inhibit immune cell activation through multiple mechanisms and therefore represents a targetable glycoimmune checkpoint. Since these glycans are not canonically druggable, we designed an αHER2 antibody–sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells. In syngeneic breast cancer models, desialylation enhanced immune cell infiltration and activation and prolonged the survival of mice, an effect that was dependent on expression of the Siglec-E checkpoint receptor found on tumor-infiltrating myeloid cells. Thus, antibody–sialidase conjugates represent a promising modality for glycoimmune checkpoint therapy.
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影响因子：
16.6
作者：
Li J;van der Wal DE;Zhu G;Xu M;Yougbare I;Ma L;Vadasz B;Carrim N;Grozovsky R;Ruan M;Zhu L;Zeng Q;Tao L;Zhai ZM;Peng J;Hou M;Leytin V;Freedman J;Hoffmeister KM;Ni H
通讯作者：
Ni H
影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
16.6
作者：
Feng, Mingye;Marjon, Kristopher D.;Weissman, Irving L.
通讯作者：
Weissman, Irving L.
影响因子：
4.4
作者：
Cohen, Merav;Elkabets, Moshe;Lichtenstein, Rachel G.
通讯作者：
Lichtenstein, Rachel G.
影响因子：
10.9
作者：
D'Amico, Lucia;Menzel, Ulrike;Zippelius, Alfred
通讯作者：
Zippelius, Alfred