Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms
Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms
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DOI：
10.1002/ijc.28400
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发表时间：
2014-02-01
影响因子：
6.4
通讯作者：
Tuereci, Oezlem
中科院分区：
文献类型：
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作者：
Woell, Stefan;Schlitter, Anna Melissa;Tuereci, Oezlem
大多数胰腺肿瘤的特点是在初步诊断后的短时间内出现致命性进展，预计患者的死亡率将进一步上升。由于缺乏有效的筛查程序和对治疗的适度反应，需要新的治疗化合物。我们研究了CLDN18.2在受影响患者中的表达，作为新抗体IMAB362潜在治疗的体外可行性研究。因此，我们分析了CLDN18.2在正常胰腺组织(N=24)、原发灶(N=202)、转移瘤(N=84)和胰腺导管腺癌(PDAC)、神经内分泌瘤(NEN)和腺泡细胞癌(N=48)中的表达。建立了一种标准化的免疫组织化学评价方法。由两个独立的评分者对特异性染色进行评价，并对染色强度(范围0-3+)和肿瘤细胞的相对比例进行分析。103例(59.2%)原发PDAC阳性。绝大多数阳性标本高表达CLDN18.2：54.6%(N=95)，染色强度为2+。NEN阳性率为20%(均为2+)。胰腺肿瘤的转移率也很高(69.4%的淋巴转移和65.7%的肝转移)。CLDN18.2在胰腺肿瘤中的阳性率很高，因此CLDN18.2的表达不仅限于原发肿瘤，而且在转移后也能保持。因此，相当数量的胰腺肿瘤患者原则上有资格接受CLDN18.2靶向治疗。有什么新消息？尽管不断努力开发新的治疗方法，胰腺导管腺癌(PDAC)作为胰腺肿瘤最常见的形式，仍然具有疾病进展的特点，几乎总是在很短的时间内被证明是致命的。然而，今天还没有有效的筛查程序来早期发现胰腺肿瘤。这项研究发现，相当数量的胰腺肿瘤患者原则上有资格接受以CLDN18.2为靶点的新治疗方法。这一发现具有直接影响，因为它为在临床试验中探索一种新的抗CLDN18.2抗体(IMAB362)治疗这种疾病提供了理论基础。
The majority of pancreatic neoplasms are characterized by a generally lethal progress within a short period of time after primary diagnosis and the mortality of patients is expected to increase further. Due to lack of efficient screening programs and moderate response to treatments, novel compounds for treatment are needed. We investigated the CLDN18.2 expression in affected patients as in vitro feasibility study for a potential treatment with the novel antibody IMAB362. Therefore, we analyzed the expression of CLDN18.2 in normal pancreatic tissues (N = 24), primary lesions (N = 202), metastases (N = 84) and intra-individually matched samples (N = 48) of patients with pancreatic ductal adenocarcinoma (PDAC), neuroendocrine neoplasia (NEN) and acinar cell carcinoma. A standardized method for evaluation by immunohistochemistry was developed. The specific staining was evaluated by two independent raters and analysis of staining intensities (range 0-3+) and relative proportions of tumor cells were performed. One hundred three (59.2%) samples of primary PDAC were found positive. The vast majority of positive samples were characterized to highly express CLDN18.2: 54.6% (N = 95) with staining intensities of 2+. NEN were positive in 20% of cases (all 2+). Metastases of pancreatic neoplasms were also frequently found positive with comparable high rates (69.4% of lymph node and 65.7% of liver metastases). The rate of CLDN18.2 positivity is high in pancreatic neoplasms whereby the expression is not limited to the primaries but is also maintained upon metastasis. Thus, a considerable number of patients with pancreatic neoplasms would be in principle eligible for a CLDN18.2-targeting approach.What's new? Despite ongoing efforts in developing novel treatments, pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic neoplasm, is still characterized by disease progression that almost always proves lethal within a very short period of time. Yet today no effective screening programs for early detection of pancreatic neoplasms are available. This study found that a considerable number of patients with pancreatic neoplasms would be in principle eligible for a new treatment approach targeting CLDN18.2. The finding has direct impact because it delivers the rationale for exploring a novel anti-CLDN18.2 antibody (IMAB362) for treatment of this disease in a clinical trial.