Near-infrared photoimmunotherapy targeting EGFR-Shedding new light on glioblastoma treatment.
Near-infrared photoimmunotherapy targeting EGFR-Shedding new light on glioblastoma treatment.
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DOI：
10.1002/ijc.31246
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发表时间：
2018-06-01
影响因子：
6.4
通讯作者：
Kramer-Marek G
中科院分区：
文献类型：
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作者：
Burley TA;Mączyńska J;Shah A;Szopa W;Harrington KJ;Boult JKR;Mrozek-Wilczkiewicz A;Vinci M;Bamber JC;Kaspera W;Kramer-Marek G
胶质母细胞瘤（GBM）是高级别脑肿瘤，由表皮生长因子受体（EGFR）的改变（扩增，缺失或错义突变）差异驱动，标准治疗后仅12-15个月预后不良。靶向肿瘤特异性细胞表面调节剂的干预组合沿着会聚的下游信号传导途径可能会增强治疗疗效。在此背景下，我们研究了一种新的光免疫治疗方法结合光动力治疗的细胞毒性与免疫治疗的特异性。EGFR特异性抗体（ZEGFR：03115）与酞菁染料IR 700DX结合，当用近红外光激发时产生细胞毒性反应。通过流式细胞术和共聚焦显微镜证实了ZEGFR：03115-IR 700DX EGFR特异性结合。该缀合物显示出脑中EGFR阳性GBM细胞的有效靶向。通过CellTiter-Glo ®测定在体外GBM细胞系和球状体中以及使用皮下U87-MGvIII异种移植物在体内评估缀合物的治疗潜力。此外，使用IVIS/Spectrum/CT在PIT前后对小鼠进行成像，以监测治疗反应。缀合物的结合与GBM细胞系中EGFR表达水平相关。细胞增殖试验显示受试细胞系之间存在受体依赖性反应。在施用免疫缀合物和照射后观察到EGFRvIII+ve肿瘤生长的抑制。重要的是，在对照肿瘤中未观察到这种反应。总之，ZEGFR：03115-IR 700DX在体外显示出特异性摄取，并能够在原位脑肿瘤模型中对EGFR表达进行成像。此外，概念验证体内PIT研究证明了缀合物在皮下胶质瘤异种移植物中的治疗功效。 有什么新消息吗？ 光免疫疗法结合了光动力疗法的破坏力和免疫疗法的特异性。但与光敏剂结合的单克隆抗体体积较大，难以深入肿瘤。在这里，作者将一种光敏染料附着在微小的“受体体”配体上，旨在寻找EGFR，EGFR通常在胶质母细胞瘤中过度表达。荧光体分子将染料分子带入癌细胞，当它暴露在近红外波长的光下时。它会杀死细胞。他们表明，EGFR-β体与光反应性染料结合选择性地杀死小鼠中过表达EGFR的胶质母细胞瘤细胞。
Glioblastomas (GBMs) are high‐grade brain tumors, differentially driven by alterations (amplification, deletion or missense mutations) in the epidermal growth factor receptor (EGFR), that carry a poor prognosis of just 12–15 months following standard therapy. A combination of interventions targeting tumor‐specific cell surface regulators along with convergent downstream signaling pathways may enhance treatment efficacy. Against this background, we investigated a novel photoimmunotherapy approach combining the cytotoxicity of photodynamic therapy with the specificity of immunotherapy. An EGFR‐specific affibody (ZEGFR:03115) was conjugated to the phthalocyanine dye, IR700DX, which when excited with near‐infrared light produces a cytotoxic response. ZEGFR:03115–IR700DX EGFR‐specific binding was confirmed by flow cytometry and confocal microscopy. The conjugate showed effective targeting of EGFR positive GBM cells in the brain. The therapeutic potential of the conjugate was assessed both in vitro, in GBM cell lines and spheroids by the CellTiter‐Glo® assay, and in vivo using subcutaneous U87‐MGvIII xenografts. In addition, mice were imaged pre‐ and post‐PIT using the IVIS/Spectrum/CT to monitor treatment response. Binding of the conjugate correlated to the level of EGFR expression in GBM cell lines. The cell proliferation assay revealed a receptor‐dependent response between the tested cell lines. Inhibition of EGFRvIII+ve tumor growth was observed following administration of the immunoconjugate and irradiation. Importantly, this response was not seen in control tumors. In conclusion, the ZEGFR:03115–IR700DX showed specific uptake in vitro and enabled imaging of EGFR expression in the orthotopic brain tumor model. Moreover, the proof‐of‐concept in vivo PIT study demonstrated therapeutic efficacy of the conjugate in subcutaneous glioma xenografts. What's new? Photoimmunotherapy combines the destructive power of photodynamic therapy with the specificity of immunotherapy. But monoclonal antibodies bound to photosensitizers are large, and difficult to get deep into the tumor. Here, the authors attach a photosensitive dye to tiny “affibody” ligands designed to seek out EGFR, which is often overexpressed in glioblastoma. The affibody molecule brings the dye molecules into the cancer cells, and when it is exposed to near‐infrared wavelengths of light. It kills the cell. They showed that the EGFR‐affibody combined with the photoreactive dye selectively kills glioblastoma cells overexpressing EGFR in mice.
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影响因子：
12.4
作者：
Jing H;Weidensteiner C;Reichardt W;Gaedicke S;Zhu X;Grosu AL;Kobayashi H;Niedermann G
通讯作者：
Niedermann G
影响因子：
9.7
作者：
Sato K;Nagaya T;Mitsunaga M;Choyke PL;Kobayashi H
通讯作者：
Kobayashi H
影响因子：
1.8
作者：
Belykh E;Martirosyan NL;Yagmurlu K;Miller EJ;Eschbacher JM;Izadyyazdanabadi M;Bardonova LA;Byvaltsev VA;Nakaji P;Preul MC
通讯作者：
Preul MC
影响因子：
5.7
作者：
Nakamura Y;Ohler ZW;Householder D;Nagaya T;Sato K;Okuyama S;Ogata F;Daar D;Hoa T;Choyke PL;Kobayashi H
通讯作者：
Kobayashi H
DOI：
10.1158/1078-0432.ccr-16-1400
发表时间：
2017-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Elliott JT;Marra K;Evans LT;Davis SC;Samkoe KS;Feldwisch J;Paulsen KD;Roberts DW;Pogue BW
通讯作者：
Pogue BW