Sharkey R M, Gold D V, Aninipot R, Vagg R, Ballance C, Newman E S, Ostella F, Hansen H J, Goldenberg D M
Center for Molecular Medicine and Immunology, University of Medicine and Dentistry of New Jersey, Newark.
Cancer Res. 1990 Feb 1;50(3 Suppl):828s-834s.
Tumor targeting of five radioiodinated murine monoclonal antibodies (MAbs) directed against human colorectal cancer were studied in nude mice bearing the GW-39 human colonic tumor xenograft. All of the MAbs are of the IgG1 isotype. Two of the MAbs (NP-4 and MN-14) are directed against a Class III carcinoembryonic antigen-specific epitope, but they differ 10-fold in their affinity. The other three MAbs recognize mucins found in colonic cancer. Mu-9 recognizes a peptide determinant similar to that described previously for a polyclonal goat anti-colon-specific antigen p. G9 identifies an organ-specific, tumor-associated carbohydrate epitope. The tumor targeting of these MAbs was compared to that of B72.3, another anti-mucin MAb. The tumor uptake of all the MAbs were similar on days 1, 3, and 7, with an average maximum accretion of between 30 and 40%/g tumor occurring by day 3. This tumor uptake was maintained for 14 days with the anti-mucin MAbs, whereas the percentage of injected dose/g in the tumor for 2 anti-carcinoembryonic antigen MAbs decreased 2-fold by day 14. Although no statistical difference could be found between the percentage of injected dose/g in the tumor for NP-4 and MN-14 (carcinoembryonic antigen MAbs), in a paired-labeled study using 131I-MN-14 and 125I-NP-4, MN-14 uptake in the tumor was consistently 1.3 times higher than that of NP-4 on all days tested. F(ab')2 fragments showed lower tumor uptake (maximum uptake for NP-4 and Mu-9 was 11% on day 1), but the faster clearance resulted in a 4- to 40-fold increase in tumor/blood ratios on day 3 in comparison to the whole IgGs. Fab' fragments had the lowest tumor uptake of the 3 forms of immunoglobulin, with a maximum of only 5%/g 6 h after injection. However, tumor/blood ratios on day 1 for the Fab' fragments were improved 3-fold over that of F(ab')2. All of these MAbs, except Mu-9, identify epitopes that can be detected in plasma, but none of the MAbs complexed appreciably when mixed in vitro with plasma containing antigen at antigen/MAb ratios anticipated to be encountered most frequently in imaging or therapy applications in humans. However, complexation of the MAbs will occur if antigen in the plasma is markedly elevated. These studies suggest that if used clinically, tumor targeting of colorectal cancer with any of these MAb IgG may be similar if these antigens are present at relatively similar concentrations in tumor.(ABSTRACT TRUNCATED AT 400 WORDS)
在携带GW - 39人结肠肿瘤异种移植的裸鼠中研究了五种针对人结肠直肠癌的放射性碘化鼠单克隆抗体（MAb）的肿瘤靶向性。所有单克隆抗体均为IgG1同种型。其中两种单克隆抗体（NP - 4和MN - 14）针对III类癌胚抗原特异性表位，但它们的亲和力相差10倍。另外三种单克隆抗体识别结肠癌中发现的粘蛋白。Mu - 9识别一种与先前描述的多克隆山羊抗结肠特异性抗原p相似的肽决定簇。G9识别一种器官特异性、肿瘤相关的碳水化合物表位。将这些单克隆抗体的肿瘤靶向性与另一种抗粘蛋白单克隆抗体B72.3进行了比较。在第1、3和7天，所有单克隆抗体的肿瘤摄取相似，到第3天肿瘤平均最大积聚量在30%至40%/克肿瘤之间。抗粘蛋白单克隆抗体的这种肿瘤摄取维持了14天，而两种抗癌胚抗原单克隆抗体在肿瘤中的注射剂量/克百分比到第14天下降了2倍。尽管在肿瘤中的注射剂量/克百分比方面，NP - 4和MN - 14（癌胚抗原单克隆抗体）之间未发现统计学差异，但在使用131I - MN - 14和125I - NP - 4的配对标记研究中，在所有测试的日子里，MN - 14在肿瘤中的摄取始终比NP - 4高1.3倍。F(ab')2片段显示出较低的肿瘤摄取（NP - 4和Mu - 9在第1天的最大摄取量为11%），但更快的清除导致与完整IgG相比，在第3天肿瘤/血液比值增加了4至40倍。Fab'片段在三种免疫球蛋白形式中肿瘤摄取最低，注射后6小时最大仅为5%/克。然而，Fab'片段在第1天的肿瘤/血液比值比F(ab')2提高了3倍。除Mu - 9外，所有这些单克隆抗体识别的表位均可在血浆中检测到，但在体外以预期在人类成像或治疗应用中最常遇到的抗原/单克隆抗体比例与含有抗原的血浆混合时，没有一种单克隆抗体明显形成复合物。然而，如果血浆中的抗原明显升高，单克隆抗体将会形成复合物。这些研究表明，如果临床使用，若这些抗原在肿瘤中的浓度相对相似，用这些单克隆抗体IgG中的任何一种靶向结肠癌的肿瘤情况可能相似。（摘要截短于400字）
