Challita-Eid P M, Abboud C N, Morrison S L, Penichet M L, Rosell K E, Poles T, Hilchey S P, Planelles V, Rosenblatt J D
Hematology-Oncology Unit, University of Rochester Cancer Center, NY 14642, USA.
J Immunol. 1998 Oct 1;161(7):3729-36.
The successful eradication of cancer cells in the setting of minimal residual disease may require targeting of metastatic tumor deposits that evade the immune system. We combined the targeting flexibility and specificity of mAbs with the immune effector function of the chemokine RANTES to target established tumor deposits. We describe the construction of an Ab fusion molecule with variable domains directed against the tumor-associated Ag HER2/neu, linked to sequences encoding the chemokine RANTES (RANTES.her2.IgG3). RANTES is a potent chemoattractant of T cells, NK cells, monocytes, and dendritic cells, and expression of RANTES has been shown to enhance immune responses against tumors in murine models. RANTES.her2.IgG3 fusion protein bound specifically to HER2/neu Ag expressed on EL4 cells and on SKBR3 breast cancer cells as assayed by flow cytometry. RANTES.her2.IgG3 could elicit actin polymerization of THP-1 cells and transendothelial migration of primary T lymphocytes. RANTES.her2.IgG3 prebound to SKBR3 cells also facilitated migration of T cells. RANTES.her2.IgG3 bound specifically to the CCR5 chemokine receptor, as demonstrated by flow cytometry, and inhibited HIV-1 infection via the CCR5 coreceptor. RANTES.her2.IgG3, alone or in combination with other chemokine or cytokine fusion Abs, may be a suitable reagent for recruitment and activation of an expanded repertoire of effector cells to tumor deposits.
在微小残留病的情况下成功根除癌细胞可能需要靶向那些逃避免疫系统的转移性肿瘤沉积物。我们将单克隆抗体（mAbs）的靶向灵活性和特异性与趋化因子RANTES的免疫效应功能相结合，以靶向已形成的肿瘤沉积物。我们描述了一种抗体融合分子的构建，其可变结构域针对肿瘤相关抗原HER2/neu，并与编码趋化因子RANTES的序列相连（RANTES.her2.IgG3）。RANTES是T细胞、自然杀伤细胞、单核细胞和树突状细胞的有效趋化剂，并且在小鼠模型中，RANTES的表达已被证明可增强针对肿瘤的免疫反应。通过流式细胞术检测，RANTES.her2.IgG3融合蛋白能特异性结合EL4细胞和SKBR3乳腺癌细胞上表达的HER2/neu抗原。RANTES.her2.IgG3可引发THP-1细胞的肌动蛋白聚合以及原代T淋巴细胞的跨内皮迁移。预先结合到SKBR3细胞上的RANTES.her2.IgG3也促进T细胞的迁移。通过流式细胞术证明，RANTES.her2.IgG3能特异性结合CCR5趋化因子受体，并通过CCR5共受体抑制HIV-1感染。RANTES.her2.IgG3单独使用或与其他趋化因子或细胞因子融合抗体联合使用，可能是一种适合招募和激活多种效应细胞至肿瘤沉积物的试剂。
