An antibody-drug conjugate targeting a GSTA glycosite-signature epitope of MUC1 expressed by non-small cell lung cancer.
An antibody-drug conjugate targeting a GSTA glycosite-signature epitope of MUC1 expressed by non-small cell lung cancer.
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一种针对非小细胞肺癌表达的 MUC1 GSTA 糖位点特征表位的抗体-药物偶联物
DOI：
10.1002/cam4.3554
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发表时间：
2020-12
期刊：
影响因子：
4
通讯作者：
Zhou D
中科院分区：
文献类型：
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作者：
Pan D;Tang Y;Tong J;Xie C;Chen J;Feng C;Hwu P;Huang W;Zhou D
针对异常糖化蛋白的抗体在治疗癌症方面是无效的。抗体-药物偶联物已成为有效的替代方案，促进肿瘤特异性药物的递送。先前的研究已经评估了MUC1糖蛋白异常糖基化串联重复区域作为与单克隆抗体结合的三个位点特异性糖基化新抗原肽基序（PDTR， GSTA和GVTS）。本研究旨在基于针对上述三种新抗原肽基序的单克隆抗体，开发用于癌症治疗的抗体-药物偶联物。通过免疫荧光染色和活细胞中溶酶体标记共定位来评估单克隆抗体的内化。免疫组化检测肿瘤及瘤周组织样本抗体阳性。用不同的癌细胞系和小鼠肿瘤异种移植模型来评估抗MUC1 adc的功效。通过将GSTA新抗原特异性16A与单甲基耳抑素E （MMAE）偶联合成抗MUC1 ADC，该ADC对多种肿瘤细胞具有较强的抗肿瘤作用，IC50范围为0.2 ~ 49.4 nM。在体内，16A‐MMAE以剂量依赖的方式抑制了NCI‐H838非小细胞肺癌细胞系建立的小鼠异种移植模型中的肿瘤生长，最低有效剂量为1mg /kg。在3mg /kg剂量下，16A‐MMAE对表达人MUC1的转基因小鼠没有显著毒性。16A‐MMAE的高抗肿瘤效果表明，异常糖基化MUC1新抗原是开发adc治疗各种癌症的潜在靶点。个体化治疗可以通过这种糖基特异性adc来实现。在这项研究中，我们描述了一种抗MUC1抗体-药物偶联物，16A -单甲基auristatin E （MMAE）。16A‐MMAE在多种类型的癌症中显示出强大的抗肿瘤活性，这表明通过翻译后修饰产生的新抗原是抗体‐药物开发的有希望的靶点。
Antibodies targeting aberrantly glycosylated proteins are ineffective in treating cancer. Antibody‐drug conjugates have emerged as effective alternatives, facilitating tumor‐specific drug delivery. Previous studies have assessed the aberrantly glycosylated tandem repeat region of MUC1 glycoprotein as three site‐specific glycosylated neoantigen peptide motifs (PDTR, GSTA, and GVTS) for binding with a monoclonal antibody. This study aimed to develop an antibody‐drug conjugate for cancer treatment based on monoclonal antibodies against the aforementioned three neoantigen peptide motifs. Internalization of monoclonal antibodies was assessed via immunofluorescence staining and colocalization with lysosomal markers in live cells. Antibody positivity in tumor and peritumoral tissue samples was assessed via immunohistochemistry. The efficacy of anti‐MUC1 ADCs was evaluated using various cancer cell lines and a mouse tumor xenograft model. An anti‐MUC1 ADC was synthesized by conjugating GSTA neoantigen‐specific 16A with monomethyl auristatin E (MMAE), which displayed potent antitumoral efficacy with an IC50 ranging 0.2–49.4 nM toward various cancer cells. In vivo, 16A‐MMAE inhibited tumor growth in a dose‐dependent manner in a mouse xenograft model established using the NCI‐H838 NSCLC cell line, at a minimum effective dose of 1 mg/kg. At 3 mg/kg, 16A‐MMAE did not cause significant toxicity in a transgenic mouse expressing human MUC1. The high antitumoral efficacy of 16A‐MMAE suggests that aberrant glycosylated MUC1 neoantigen is a potential target for the development of ADCs for treating various cancers. Personalized therapy may be achieved through such glycosite‐specific ADCs. In this study, we describe an anti‐MUC1 antibody‐drug conjugate, 16A‐monomethyl auristatin E (MMAE). 16A‐MMAE showed potent antitumoral activity in multiple types of cancer, suggesting that neoantigens generated by posttranslational modification are promising targets for antibody‐drug development.
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影响因子：
--
作者：
Adil Butt M;Pye H;Haidry RJ;Oukrif D;Khan SU;Puccio I;Gandy M;Reinert HW;Bloom E;Rashid M;Yahioglu G;Deonarain MP;Hamoudi R;Rodriguez-Justo M;Novelli MR;Lovat LB
通讯作者：
Lovat LB
影响因子：
11.5
作者：
Gray, Jhanelle E.;Heist, Rebecca S.;Goldenberg, David M.
通讯作者：
Goldenberg, David M.
影响因子：
8
作者：
Panchamoorthy, Govind;Jin, Caining;Kufe, Donald
通讯作者：
Kufe, Donald
影响因子：
4.7
作者：
Hamann, PR;Hinman, LM;Bernstein, I
通讯作者：
Bernstein, I
DOI：
10.1186/bcr2841
发表时间：
2011-03-08
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Blixt O;Bueti D;Burford B;Allen D;Julien S;Hollingsworth M;Gammerman A;Fentiman I;Taylor-Papadimitriou J;Burchell JM
通讯作者：
Burchell JM