Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors
Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors
复制标题
DOI：
10.1158/1535-7163.mct-05-0488
复制
发表时间：
2006-04-01
影响因子：
5.7
通讯作者：
Penichet, ML
中科院分区：
文献类型：
--
作者：
Helguera, G;Rodríguez, JA;Penichet, ML
我们之前已经生成了与白细胞介素-2 （IL-21、IL-12）或粒细胞巨噬细胞集落刺激因子（GMCSF）[单功能融合蛋白（mono-AbFP）]或与IL-2和IL-12或IL-12和GM-CSF[双功能融合蛋白（bi-AbFPI）]融合的抗人HER2/去人源化IgG3。这些abfp保留了细胞因子和抗原结合活性。我们现在进一步表征了abfp，并确定了融合细胞因子的肝素结合活性，它们触发ifn - γ分泌和自然杀伤（NK）激活的能力，以及它们的直接抗肿瘤功效。流式细胞术显示含有IL-12和IL-2的AbFPs具有肝素结合活性，尽管这种活性在双AbFPs中似乎有所降低。然而，两种双abfp都保留了刺激NK细胞系key -1中IL-12依赖性IFN-y分泌的能力，并且IL-12/IL-2双abfp诱导脾细胞中NK活性。在三种不同的人HER2/neu小鼠同源模型（D2F2/E2、CT26-HER2/neu和MC38-HER2/neu）刺激的小鼠中，研究了双abfp和单abfp组合的抗肿瘤效果。尽管在不同的肿瘤模型中观察到抗肿瘤反应的显著差异，但IL-12和GM-CSF单abfps联合使用可以保护100%的D2F2/ e2攻击小鼠和75%的CT26-HER2/ new攻击小鼠。相比之下，双abfps的保护效果不如单abfps的组合，在某些模型中，甚至不如单abfps。然而，在所有病例中，大多数长期幸存者在sc再挑战肿瘤和后来不表达HER2/neu的亲代肿瘤后表现出保护作用。这些结果表明，尽管保护模式依赖于肿瘤模型，但abfp治疗可以有效地对表达HER2/neu的腹膜肿瘤产生高水平的保护，这可能与卵巢癌、结肠癌、胃癌、膀胱癌、肺癌和乳腺癌的原发性或转移性腹膜癌有关。
We have previously generated antihuman HER2/neuhumanized IgG3 fused to interleukin-2 (IL-21, IL-12, or granulocyte macrorphage colony-stimulating factor (GMCSF) [monofunctional fusion proteins (mono-AbFP)] or fused to IL-2 and IL-12 or IL-12 and GM-CSF [bifunctional fusion proteins (bi-AbFPI)]. These AbFPs retained cytokine and antigen-binding activities. We have now further characterized the AbFPs and determined the heparin-binding activity of the fused cytokines, their ability to trigger IFN-gamma secretion and natural killer (NK) activation, and their direct antitumor efficacy. Flow cytometry revealed heparin-binding activity in the AbFPs containing IL-12 and IL-2, although this activity seems to be decreased in the bi-AbFPs. However, both bi-AbFPs retained the capacity to stimulate IL-12-dependent IFN-y secretion in the NK cell line KY-1, and IL-12/IL-2 bi-AbFP induced NK activity in splenocytes. The antitumor effectiveness of bi-AbFPs and mono-AbFP combinations was studied in mice challenged i.p. with three different human HER2/neu murine syngeneic models (D2F2/E2, CT26-HER2/neu, and MC38-HER2/neu). Although a significant variability in the profile of antitumor response was observed in the different tumor models, the combination of IL-12 and GM-CSF mono-AbFPs protected 100% of D2F2/E2-challenged and 75% of CT26-HER2/neu-challenged mice. In contrast, bi-AbFPs protected less than the combination of mono-AbFPs and, in some models, even less than mono-AbFPs alone. However, in all cases, most of long-term survivors showed protection after s.c. rechallenge with the tumors and later with the parental tumors not expressing HER2/neu. These results show that, although the pattern of protection is tumor model dependent, treatments with AbFPs can effectively generate high levels of protection against peritoneal tumors expressing HER2/neu, which may be relevant in patients with primary or metastatic peritoneal carcinomatosis that may be observed in ovarian, colon, stomach, bladder, lung, and breast cancers.