靶向癌症特异性 LYPD3 糖型治疗肿瘤

Theresa Neumann, Evelyn Hartung, Johanna Gellert, Lisa Weiss, Manon Weiske, Naomi Kast, Stephanie Gurka, Sophie Marinoff, Anika Jäkel, A. Danielczyk, Patrik Kehler
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摘要

导言癌症中最剧烈的变化之一是蛋白质和脂质的糖基化改变,从而产生截短的 O 型糖,如正常细胞中几乎不存在的汤姆森-弗里登雷希(TF)或汤姆森-新(Tn)抗原。由于这些特异性聚糖具有极好的肿瘤特异性和广泛的癌症表达,因此由这些特异性聚糖组成的蛋白质-碳水化合物表位组合是强效靶向疗法的理想候选物:我们制备了 GT-002,这是一种单克隆抗体,仅在存在 TF 糖基化的情况下特异性地靶向上皮糖蛋白 LYPD3。在 ELISA 和流式细胞术中,它不会与非糖基化的 LYPD3 或其他糖蛋白上的 TF 发生交叉反应。GT-002 能与多种肿瘤细胞系结合,并能染色不同癌症适应症的肿瘤组织,包括头颈部鳞状细胞癌。在对包括多个 LYPD3 阳性器官在内的正常人体组织面板进行的免疫组化研究中,GT-002 几乎完全消除了与正常组织的结合,从而证实了其显著的肿瘤特异性。因此,与 Lupartumab 相比,我们观察到 GT-002 与正常人体组织的结合明显减少,而 Lupartumab 是一种传统的抗 LYPD3 抗体,以前曾作为抗体药物共轭物(BAY1129980)用于临床开发。对健康组织进行神经氨酸酶处理,导致硅氨酸残基裂解,重新建立了 GT-002 与 Lupartumab 的结合,表明 GT-002 表位在正常细胞中被硅氨酸掩盖:我们认为,GT-002是开发抗体-药物-放射共轭物以及双特异性分子和嵌合抗原受体疗法的有希望的候选药物,并突出了针对蛋白质-碳水化合物联合表位的抗体在降低靶上/靶外肿瘤细胞毒性方面的强大潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting a cancer-specific LYPD3 glycoform for tumor therapy
Introduction: One of the most drastic changes in cancer is the altered glycosylation of proteins and lipids, giving rise to truncated O-glycans like the Thomsen Friedenreich (TF) or Thomsen nouvelle (Tn) antigen, which are almost absent on normal cells. Combined protein-carbohydrate epitopes comprising these specific glycans are ideal candidates for potent targeted therapies given their excellent tumor specificity and broad cancer expression.Methods and results: We have generated GT-002, a monoclonal antibody specifically targeting the epithelial glycoprotein LYPD3 only in the presence of a TF glycosylation. It does not cross-react with non-glycosylated LYPD3 or TF on other glycoproteins in ELISA and flow cytometry. GT-002 binds to various tumor cell lines and stains tumor tissues of different cancer indications including squamous cell carcinoma of the head and neck. The remarkable tumor specificity was confirmed in an immunohistochemistry study on a normal human tissue panel including several LYPD3-positive organs, where GT-002 elicited almost completely abolished normal tissue binding. Consequently, we observed markedly reduced binding of GT-002 to normal human tissues compared to Lupartumab, a conventional anti-LYPD3 antibody previously in clinical development as antibody-drug conjugate (BAY1129980). Neuraminidase treatment of healthy tissues, resulting in cleavage of sialic acid residues, re-established binding of GT-002 comparable to Lupartumab, showing that the GT-002 epitope is masked by sialic acid in normal cells.Discussion: We believe that GT-002 is a promising candidate for development of antibody-drug- and radio-conjugates as well as bispecific molecules and chimeric antigen receptor therapeutics and highlights the powerful potential of antibodies against combined protein-carbohydrate epitopes to reduce on-target/off-tumor cytotoxicity.
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