Anti-idiotype x anti-CD44 bispecific antibodies inhibit invasion of lymphoid organs by B cell lymphoma
Anti-idiotype x anti-CD44 bispecific antibodies inhibit invasion of lymphoid organs by B cell lymphoma
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DOI：
10.4049/jimmunol.173.7.4736
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发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Hollander, N
中科院分区：
文献类型：
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作者：
Avin, E;Haimovich, J;Hollander, N
针对黏附分子的抗体可以阻断肿瘤转移，这表明它们可用于治疗。然而，这类抗体也会影响非恶性细胞。为了避免这种不良反应，我们建议使用同时与黏附受体和肿瘤特异性抗原结合的双特异性抗体。与正常细胞相比，这种双功能抗体更能与同时表达靶抗原的肿瘤细胞结合。恶性B淋巴细胞表面免疫球蛋白ID是一种肿瘤特异性抗原。因此，我们制备了针对黏附分子CD44和针对小鼠B细胞淋巴瘤的独特型决定簇38C-13的双特异性抗体。这些抗ID x抗CD44双特异性抗体阻断了38C-13细胞与透明质酸的黏附，而不影响ID阴性细胞的黏附。体内研究表明，双特异性抗体抑制淋巴瘤细胞向淋巴结、骨髓和脾的扩散，延长荷瘤小鼠的生存时间。双特异性抗体可抑制38C-13细胞向淋巴器官的迁移。因此，双特异性抗体介导的转移减少至少部分是由于减少了对这些器官的归巢。与抗CD44单特异性抗体相比，抗ID x抗CD44双特异性抗体不影响迟发型超敏反应等免疫反应。因此，针对黏附分子和肿瘤特异性AGS的双特异性抗体可能会选择性地阻止肿瘤转移，从而可能至少保留部分免疫系统的完整性。
The demonstration that Abs to adhesion molecules can block tumor metastasis suggested their use for therapy. However, such Abs affect nonmalignant cells as well. To circumvent this adverse effect, we proposed the use of bispecific Abs that bind simultaneously to an adhesion receptor and to a tumor-specific Ag. Such bifunctional Abs bind more avidly to tumor cells that coexpress both target Ags than to normal cells. The Id of the surface Ig of malignant B lymphocytes is a tumor-specific Ag. Therefore, we produced bispecific Abs with specificity to the adhesion molecule, CD44, and to an idiotypic determinant of the murine B cell lymphoma, 38C-13. These anti-Id x anti-CD44 bispecific Abs blocked 38C-13 cell adhesion to hyaluronic acid, while not affecting adhesion of Id-negative cells. In vivo studies demonstrated that the bispecific Abs inhibited lymphoma cell dissemination to the lymph nodes, bone marrow, and spleen, and prolonged survival of tumor-bearing mice. Migration of 38C-13 cells to the lymphoid organs was inhibited by the bispecific Abs. Thus, the bispecific Ab-mediated reduction in metastasis resulted, at least in part, from reduced homing to these organs. In contrast to anti-CD44 monospecific Abs, the anti-Id x anti-CD44 bispecific Abs did not affect immune responses such as delayed-type hypersensitivity. Hence, bispecific Abs against adhesion molecules and tumor-specific Ags may selectively block tumor metastasis in a way which may leave at least part of the immune system intact.