Boxer G M, Abassi A M, Pedley R B, Begent R H
University Department of Clinical Oncology, Royal Free Hospital School of Medicine, London, UK.
Br J Cancer. 1994 Feb;69(2):307-14. doi: 10.1038/bjc.1994.56.
Antibody targeting has potential for selective delivery of cancer therapy. However, there is a wide variation in the degree of antibody localisation in individual patients with colorectal adenocarcinoma. Colorectal adenocarcinomas are composed of glandular structures separated from fibrovascular stroma by a basal lamina which may represent a significant barrier to extravasated antibody. Basement membrane-associated CEA epitopes may be more accessible to antibodies than those which are cytoplasmic or lumenal. We have investigated by immunohistochemistry and in vivo localisation, the extent to which distribution of antigen epitopes influences targeting. Two monoclonal antibodies (A5B7 and EA77) recognising non-overlapping CEA epitopes were reacted immunohistochemically with samples of 39 tumours. Intensity and site of reaction were assessed for basement membrane, cytoplasmic or lumenal surface association. 125I-labelled antibodies were injected into nude mice bearing LS174T tumour. Per cent injected activity per gram was measured in tumour and normal tissues, 24, 72 and 168 h later. Tissues reacted immunohistochemically for CEA were autoradiographed to assess the relationship of injected antibody to target antigen. Immunohistochemistry showed that A5B7 antibody favours basement membrane aspects of malignant glands; in contrast, EA77 concentrated generally on lumenal surfaces. In vivo localisation showed that per cent inj.act g-1 in tumour for A5B7 reached 36.5% at 24 h. EA77 localised to a lesser extent (9.1% at 24 h), despite a longer circulatory half-life. Autoradiography combined with immunohistochemistry showed A5B7 reacting with antigen close to vasculature after 24 h, slowly penetrating deeper parts of the tumour by 72 h. In contrast, EA77 was confined mainly to fibrovascular stroma, showing little labelling of antigen-positive tumour cells. Localisation differences between A5B7 and EA77 may partly be due to accessibility of epitopes on tumour cells.
抗体靶向具有实现癌症治疗选择性递送的潜力。然而，在患有结肠直肠腺癌的个体患者中，抗体定位程度存在很大差异。结肠直肠腺癌由腺管结构组成，其通过基膜与纤维血管基质分隔开，基膜可能是渗出抗体的重要屏障。与基底膜相关的癌胚抗原（CEA）表位可能比那些位于细胞质或管腔中的表位更容易被抗体识别。我们通过免疫组织化学和体内定位研究了抗原表位的分布对靶向作用的影响程度。两种识别不重叠CEA表位的单克隆抗体（A5B7和EA77）与39个肿瘤样本进行免疫组织化学反应。评估基底膜、细胞质或管腔表面结合的反应强度和部位。将125I标记的抗体注射到携带LS174T肿瘤的裸鼠体内。在24、72和168小时后测量肿瘤和正常组织中每克注射活性的百分比。对经免疫组织化学反应的CEA组织进行放射自显影，以评估注射抗体与靶抗原的关系。免疫组织化学显示，A5B7抗体倾向于恶性腺管的基底膜部分；相比之下，EA77通常集中在管腔表面。体内定位显示，A5B7在24小时时肿瘤中每克注射活性百分比达到36.5%。尽管EA77的循环半衰期更长，但其定位程度较低（24小时时为9.1%）。放射自显影与免疫组织化学相结合显示，24小时后A5B7与靠近血管的抗原发生反应，到72小时时缓慢渗透到肿瘤的更深部位。相比之下，EA77主要局限于纤维血管基质，几乎没有标记抗原阳性的肿瘤细胞。A5B7和EA77之间的定位差异可能部分归因于肿瘤细胞上表位的可及性。
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