Targeting CD133high Colorectal Cancer Cells In Vitro and In Vivo With an Asymmetric Bispecific Antibody
Targeting CD133high Colorectal Cancer Cells In Vitro and In Vivo With an Asymmetric Bispecific Antibody
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使用不对称双特异性抗体在体外和体内靶向 CD133high 结直肠癌细胞
DOI：
10.1097/cji.0000000000000086
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Tao Zhang
中科院分区：
文献类型：
--
作者：
Tao Wang;Jing Zhang;Yang Liu;Tao Zhang
晚期结直肠癌(CRC)治疗的一个关键障碍是传统化疗对生存率的改善不足。据报道，癌症干细胞是关键的解释之一。CD133已被确定为结直肠癌干细胞的表面标志。针对肿瘤特异性抗原的双特异性抗体(BiAbbs)是一种很有前途的治疗恶性肿瘤的药物，但针对CD133的基因工程研究尚未见报道。本研究采用免疫组织化学方法检测CD133在原发结直肠癌中的表达，并研制了一种由嵌合单抗AC133和人源化OKT3单链组成的不对称双抗，在体内外通过武装活化的T细胞来杀伤表达CD133的肿瘤细胞。在免疫组织化学检查中，CD133的过度表达(50%的染色细胞)与淋巴侵犯和临床分期显著相关。新分子对CD133和CD3具有双重抗原结合特异性，其独特的结构不仅便于纯化，而且使抗体具有更长时间和更强的细胞毒活性。通过武装活化的T细胞，新抗体在体外对CD133高水平而对CD133低水平的CRC细胞表现出令人印象深刻的细胞毒性，产生大量的细胞因子(干扰素和粒-巨噬细胞集落刺激因子)，并能抑制非肥胖糖尿病-严重联合免疫缺陷小鼠的肿瘤生长和延缓肿瘤的发展，而没有明显的毒性。综上所述，新的BiAb具有繁荣的特性，支持该分子有潜力成为治疗结直肠癌的新疗法的潜在候选者。
A critical obstacle in advanced colorectal cancer (CRC) treatment is the insufficient improvement on survival of conventional chemotherapy. Cancer stem cells are reported to be one of the crucial explanations. CD133 has been identified as a surface marker of CRC stem cells. Bispecific antibodies (BiAbs) targeting tumor-specific antigens are promising therapeutics for malignant diseases, yet that targeting CD133 produced by genetic engineering has not been published. In the current research, CD133 expression in primary CRC was detected by immunohistochemistry, and an asymmetric BiAb consisting of monomer of chimeric AC133 (mouse anti-human CD133 monoclonal antibody) and single chain of humanized OKT3 was developed to eradicate CD133-expressing tumor cells by arming activated T cells in vitro and in vivo. In immunohistochemical examination, CD133 overexpression (>50% of stained cells) frequency was significantly correlated with lymphatic invasion and clinical stage. The new molecular revealed dual-antigen–binding specificity to CD133 and CD3, its distinct structure not only facilitated the purification procedure but also conferred the antibody to ensure a longer and stronger cytotoxic activity. By arming activated T cells, the new antibody displayed impressive cytotoxicity toward CD133high but not CD133low CRC cells in vitro, produced amounts of cytokines (interferon-&ggr; and granulocyte-macrophage colony–stimulating factor), and could inhibit tumor growth and retard tumor development in nonobese diabetic-severe combined immunodeficient mice without apparent toxicity. Taken together, the new BiAb possesses prosperities that support that the molecule has the potential of being a promising candidate of new therapeutics for CRC therapy.
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影响因子：
8.8
作者：
Smith, L. M.;Nesterova, A.;Ryan, M. C.;Duniho, S.;Jonas, M.;Anderson, M.;Zabinski, R. F.;Sutherland, M. K.;Gerber, H-P;Van Orden, K. L.;Moore, P. A.;Ruben, S. M.;Carter, P. J.
通讯作者：
Carter, P. J.
DOI：
10.1073/pnas.1215438110
发表时间：
2013-04-02
影响因子：
11.1
作者：
Arndt, Kathrin;Grinenko, Tatyana;Waskow, Claudia
通讯作者：
Waskow, Claudia
DOI：
10.1891/9780826121646.0002
发表时间：
2018-09
期刊：
Cancer Rehabilitation
影响因子：
--
作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
通讯作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
DOI：
--
发表时间：
2009
期刊：
--
影响因子：
--
作者：
Xiaowei Sun;R. Essalmani;N. Seidah;A. Prat
通讯作者：
Xiaowei Sun;R. Essalmani;N. Seidah;A. Prat
影响因子：
5.7
作者：
J. Christiansen;A. Rajasekaran
通讯作者：
J. Christiansen;A. Rajasekaran