Enhanced inhibition of murine tumor and human breast tumor xenografts using targeted delivery of an antibody-endostatin fusion protein
Enhanced inhibition of murine tumor and human breast tumor xenografts using targeted delivery of an antibody-endostatin fusion protein
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DOI：
10.1158/1535-7163.mct-04-0321
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发表时间：
2005-06-01
影响因子：
5.7
通讯作者：
Shin, SU
中科院分区：
文献类型：
--
作者：
Cho, HM;Rosenblatt, JD;Shin, SU
内皮抑素可以抑制小鼠的血管生成和肿瘤生长。内皮抑素作为抗药的潜在局限性。人类肿瘤剂的特点是蛋白质的血清半衰期短，可能会降低肿瘤部位的有效浓度并需要频繁给药。为了提高抗肿瘤活性，将内皮抑素与肿瘤选择性 HER2 抗原特异性抗体融合，形成抗体-内皮抑素融合蛋白（抗 HER2 IgG3-内皮抑素）。正常内皮抑素在小鼠血清中快速清除（T-1/2(2)，= 0.6-3.8 小时），而抗 HER2 IgG3 内皮抑素具有较长的半衰期（90% 完整；T-1/2(2)，40.2-44.0 小时）。在植入 CT26 肿瘤或工程化表达 HER2 抗原的 CT26 肿瘤 (CT26-HER2) 的 BALB/c 小鼠中评估了抗 HER2 IgG3-内皮抑素的抗原特异性靶向。相对于 CT26 肿瘤，放射性碘化抗 HER2 IgG3-内皮抑素优先定位于 CT26-HER2 肿瘤。与 CT26 相比，对小鼠施用抗 HER2 IgG3-内皮抑素显示出对 CT26-HER2 肿瘤生长的优先抑制。抗 HER2 IgG3-内皮抑素还显着抑制严重联合免疫缺陷小鼠中人乳腺癌 SK-BR-3 异种移植物的生长。抗-HER2 IgG3-内皮抑素比内皮抑素、抗-HER2 IgG3抗体或抗体与内皮抑素的组合更有效地显着更有效地抑制肿瘤生长。与未治疗的CT26-HER2或用融合蛋白治疗的CT26相比，用内皮抑素融合蛋白治疗的CT26-HER2肿瘤具有降低的血管密度和分支。抗 HER2 IgG3-内皮抑素的有效性增强可能是由于更长的半衰期、改善的血清稳定性以及选择性靶向肿瘤，从而减少血管生成。将抗血管生成蛋白（例如内皮抑素）与靶向抗体连接代表了一种有前途且通用的抗肿瘤治疗方法。
Endostatin can inhibit angiogenesis and tumor growth in mice. A potential limitation of endostatin as an anti. tumor agent in humans is the short serum half-life of the protein that may decrease effective concentration at the site of tumor and necessitate frequent dosing. In an effort to improve antitumor activity, endostatin was fused to an antibody specific for the tumor-selective HER2 antigen to create an antibody-endostatin fusion protein (anti-HER2 IgG3-endostatin). Normal endostatin rapidly cleared from serum in mice (T-1/2(2), = 0.6-3.8 hours), whereas anti-HER2 IgG3-endostatin had a prolonged half-life (90% intact; T-1/2(2), 40.2-44.0 hours). Antigen-specific targeting of anti-HER2 IgG3-endostatin was evaluated in BALB/c mice implanted with CT26 tumors or CT26 tumors engineered to express the HER2 antigen (CT26-HER2). Radio-iodinated anti-HER2 IgG3-endostatin preferentially localized to CT26-HER2 tumors relative to CT26 tumors. Administration of anti-HER2 IgG3-endostatin to mice showed preferential inhibition of CT26-HER2 tumor growth compared with CT26. Anti-HER2 IgG3-endostatin also markedly inhibited the growth of human breast cancer SK-BR-3 xenografts in severe combined immunodeficient mice. Anti-HER2 IgG3-endostatin inhibited tumor growth significantly more effectively than endostatin, anti-HER2 IgG3 antibody, or the combination of antibody and endostatin. CT26-HER2 tumors treated with the endostatin fusion protein had decreased blood vessel density and branching compared with untreated CT26-HER2 or CT26 treated with the fusion protein. The enhanced effectiveness of anti-HER2 IgG3-endostatin may be due to a longer half-life, improved serum stability, and selective targeting of endostatin to tumors, resulting in decreased angiogenesis. Linking of an antiangiogenic protein, such as endostatin, to a targeting antibody represents a promising and versatile approach to antitumor therapy.