Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells.
Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells.
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DOI：
10.1007/s00262-008-0607-1
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发表时间：
2009-06
影响因子：
5.8
通讯作者：
Karagiannis, Sophia N.
中科院分区：
文献类型：
--
作者：
Karagiannis, Panagiotis;Singer, Josef;Hunt, James;Gan, Samuel K. E.;Rudman, Sarah M.;Mechtcheriakova, Diana;Knittelfelder, Regina;Daniels, Tracy R.;Hobson, Philip S.;Beavil, Andrew J.;Spicer, James;Nestle, Frank O.;Penichet, Manuel L.;Gould, Hannah J.;Jensen-Jarolim, Erika;Karagiannis, Sophia N.
曲妥珠单抗（Herceptin®）是一种针对人表皮生长因子受体2 （HER2/neu）的人源化IgG1抗体，是临床用于治疗乳腺癌的主要抗体。临床前证据和临床研究表明，曲妥珠单抗采用几种抗肿瘤机制，最有可能有助于提高HER2/新阳性乳腺癌患者的生存率。新的策略旨在改善基于抗体的治疗方法，如曲妥珠单抗，例如通过增强抗体介导的效应功能机制。基于我们之前的发现，与相应的IgG1抗体相比，嵌合卵巢肿瘤抗原特异性IgE抗体在肿瘤细胞杀伤方面表现出更大的功效，我们已经生产了曲妥珠单抗的IgE同源物。曲妥珠单抗IgE被设计成与曲妥珠单抗相同的轻链和重链可变区，但用epsilon代替γ -1重链恒定区。我们描述了曲妥珠单抗IgE的物理特征和配体结合特性，并在功能分析中阐明了其潜在的抗肿瘤活性。曲妥珠单抗和曲妥珠单抗IgE都可以激活单核细胞杀死肿瘤细胞，但它们通过不同的机制起作用：曲妥珠单抗作用于抗体依赖性细胞介导的吞噬（ADCP），而曲妥珠单抗IgE作用于抗体依赖性细胞介导的细胞毒性（ADCC）。曲妥珠单抗IgE与肥大细胞和表达HER2/ new的肿瘤细胞孵育，触发肥大细胞脱颗粒，招募针对癌细胞的强效免疫反应，具有过敏反应的特征。最后，在活力测定中，两种抗体介导肿瘤细胞生长阻滞的水平相当。曲妥珠单抗IgE的这些功能特征，有些与曲妥珠单抗不同，表明其有可能补充或改善曲妥珠单抗现有的临床益处。
Trastuzumab (Herceptin®), a humanized IgG1 antibody raised against the human epidermal growth factor receptor 2 (HER2/neu), is the main antibody in clinical use against breast cancer. Pre-clinical evidence and clinical studies indicate that trastuzumab employs several anti-tumour mechanisms that most likely contribute to enhanced survival of patients with HER2/neu-positive breast carcinomas. New strategies are aimed at improving antibody-based therapeutics like trastuzumab, e.g. by enhancing antibody-mediated effector function mechanisms. Based on our previous findings that a chimaeric ovarian tumour antigen-specific IgE antibody showed greater efficacy in tumour cell killing, compared to the corresponding IgG1 antibody, we have produced an IgE homologue of trastuzumab. Trastuzumab IgE was engineered with the same light- and heavy-chain variable-regions as trastuzumab, but with an epsilon in place of the gamma-1 heavy-chain constant region. We describe the physical characterisation and ligand binding properties of the trastuzumab IgE and elucidate its potential anti-tumour activities in functional assays. Both trastuzumab and trastuzumab IgE can activate monocytic cells to kill tumour cells, but they operate by different mechanisms: trastuzumab functions in antibody-dependent cell-mediated phagocytosis (ADCP), whereas trastuzumab IgE functions in antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab IgE, incubated with mast cells and HER2/neu-expressing tumour cells, triggers mast cell degranulation, recruiting against cancer cells a potent immune response, characteristic of allergic reactions. Finally, in viability assays both antibodies mediate comparable levels of tumour cell growth arrest. These functional characteristics of trastuzumab IgE, some distinct from those of trastuzumab, indicate its potential to complement or improve upon the existing clinical benefits of trastuzumab.
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DOI：
10.1084/jem.20021806
发表时间：
2003-06-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gonzalez-Espinosa C;Odom S;Olivera A;Hobson JP;Martinez ME;Oliveira-Dos-Santos A;Barra L;Spiegel S;Penninger JM;Rivera J
通讯作者：
Rivera J
影响因子：
5.6
作者：
Gerstner, RB;Carter, P;Lowman, HB
通讯作者：
Lowman, HB
影响因子：
64.8
作者：
Cho, HS;Mason, K;Leahy, DJ
通讯作者：
Leahy, DJ
影响因子：
64.8
作者：
GEHA, RS;HELM, B;GOULD, H
通讯作者：
GOULD, H
DOI：
10.1073/pnas.89.10.4285
发表时间：
1992-05-15
影响因子：
11.1
作者：
CARTER, P;PRESTA, L;SHEPARD, HM
通讯作者：
SHEPARD, HM