Cancer-Stroma Targeting Therapy by Cytotoxic Immunoconjugate Bound to the Collagen 4 Network in the Tumor Tissue
Cancer-Stroma Targeting Therapy by Cytotoxic Immunoconjugate Bound to the Collagen 4 Network in the Tumor Tissue
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DOI：
10.1021/bc200158j
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发表时间：
2011-09-01
影响因子：
4.7
通讯作者：
Matsumura, Yasuhiro
中科院分区：
文献类型：
--
作者：
Yasunaga, Masahiro;Manabe, Shino;Matsumura, Yasuhiro
一些细胞毒性免疫偶联物已被批准用于恶性淋巴瘤，一种代表性的多血管和基质贫乏肿瘤。然而，许多人实体瘤具有丰富的细胞间基质，其阻止癌细胞特异性单克隆抗体（mAb）的扩散并成为阻止免疫缀合物直接攻击癌细胞的屏障。在这里，我们展示了一种新策略的成功开发，该策略克服了这一缺点，并通过酯键将其与针对胶原蛋白4（肿瘤基质的丰富成分）的mAb缀合，实现了拓扑异构酶I抑制剂SN 38的高度局部化浓度。聚（乙二醇）（PEG）用作间隔物，靠近每个键，以保持在血液中的稳定性。免疫缀合物选择性地从渗漏的肿瘤血管外渗，并且最低限度地从正常血管外渗，因为免疫缀合物太大而不能穿过正常血管壁。基质靶向免疫缀合物结合至基质以产生支架，细胞毒性剂从支架持续释放，并且该剂随后扩散遍及肿瘤组织以损伤肿瘤细胞和血管。因此，癌症-间质靶向免疫缀合物疗法被验证为肿瘤学疗法的新模式，特别是对于难治性、间质丰富的癌症。
Some cytotoxic immunoconjugates have been approved for malignant lymphoma, a representative of hypervascular and stroma-poor tumors. However, many human solid tumors possess abundant intercellular stromata that prevent diffusion of cancer cell-specific monoclonal antibodies (mAb) and become a barrier preventing immunoconjugates from directly attacking cancer cells. Here we show the successful development of a new strategy that overcomes this drawback and achieves a highly localized concentration of a topoisomerase I inhibitor, SN 38, by conjugating it via an ester bond to a mAb targeted against collagen 4, a plentiful component of the tumor stroma. Poly(ethylene glycol) (PEG) was utilized as a spacer, close to each bond, to maintain stability in the blood. Immunoconjugates selectively extravasated from leaky tumor vessels and minimally from normal vessels because the immunoconjugates are too large to pass through normal vessel walls. Stroma targeting immunconjugates bound to the stroma to create a scaffold, from which sustained release of cytotoxic agent occurred and the agent subsequently diffused throughout the tumor tissue to damage both tumor cells and vessels. Cancer-stroma-targeting immunoconjugate therapy was thus validated as a new modality of oncological therapy, especially for refractory, stromal-rich cancers.