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首页> 外文期刊>Journal of immunotherapy >Potent control of tumor growth by CEA/CD3-bispecific single-chain antibody constructs that are not competitively inhibited by soluble CEA.
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Potent control of tumor growth by CEA/CD3-bispecific single-chain antibody constructs that are not competitively inhibited by soluble CEA.

机译：CEA / CD3-双特异性单链抗体构建体可有效控制肿瘤生长，而可溶性CEA不能竞争性地抑制该构建体。

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摘要

Carcinoembryonic antigen (CEA, CD66e) is a well-characterized tumor-associated antigen that is frequently overexpressed in tumors. Phospholipases release CEA from tumor cells resulting in high circulating serum levels of soluble CEA (sCEA) that has been validated as marker for progression of colorectal, breast, and lung cancers. sCEA also acts as a competitive inhibitor for anticancer strategies targeting membrane-bound CEA. As a novel therapeutic approach for treatment of tumors expressing CEA on their cell surface, we constructed a series of bispecific single-chain antibodies (bscAb) combining various single-chain variable fragments recognizing human CEA with a deimmunized single-chain variable fragments recognizing human CD3. CEA/CD3-bscAbs redirected human T cells to lyse CEA-expressing tumor cells in vitro and in vivo. Efficient tumor cell lysis was achieved in vitro at bscAb concentrations from 1 pg/mL (19 fM) to 8.9 pg/mL with preactivated CD8 T cells, and 200 to 500 pg/mL with unstimulated peripheral blood mononuclear cell. The cytotoxic activity of a subset of CEA/CD3-bscAbs was not competitively inhibited by sCEA at concentrations that exceeded levels found in the serum of most cancer patients. Treatment with CEA/CD3-bscAbs prevented the growth of human colorectal cancer lines in a severe combined immunodeficiency mouse model modified to show human T cell killing of tumors. A murine surrogate CEA/CD3-bscAb capable of recruiting murine T cells for redirected tumor lysis in immunocompetent mice prevented the growth of lung tumors expressing human CEA. Together, our results reveal a unique opportunity for targeting cytotoxic T cells toward CEA-expressing tumors without being competitively inhibited by sCEA and establish CEA/CD3-bscAb as a promising and potent therapeutic approach.
机译：癌胚抗原（CEA，CD66e）是一种特征明确的肿瘤相关抗原，通常在肿瘤中过表达。磷脂酶从肿瘤细胞释放CEA，导致高循环血清可溶性CEA（sCEA）的水平，该水平已被证实可作为结直肠癌，乳腺癌和肺癌进展的标志。 sCEA还可作为针对膜结合CEA的抗癌策略的竞争性抑制剂。作为治疗在其细胞表面表达CEA的肿瘤的新型治疗方法，我们构建了一系列双特异性单链抗体（bscAb），将识别人CEA的各种单链可变片段与识别人CD3的去免疫单链可变片段相结合。 CEA / CD3-bscAbs在体外和体内将人类T细胞重定向至裂解表达CEA的肿瘤细胞。在体外，预激活的CD8 T细胞在bscAb浓度从1 pg / mL（19 fM）至8.9 pg / mL的bscAb和在未刺激的外周血单核细胞的200-500 pg / mL的条件下实现了有效的肿瘤细胞裂解。当浓度超过大多数癌症患者血清中发现的水平时，sCEA不能竞争性地抑制一部分CEA / CD3-bscAb的细胞毒活性。 CEA / CD3-bscAbs的治疗在严重的联合免疫缺陷小鼠模型中阻止了人类结直肠癌系的生长，该小鼠模型经修饰可显示出人类T细胞对肿瘤的杀伤作用。能够替代小鼠T细胞的小鼠替代性CEA / CD3-bscAb可在免疫活性小鼠中重定向肿瘤溶解，从而阻止了表达人CEA的肺肿瘤的生长。总之，我们的结果揭示了将细胞毒性T细胞靶向表达CEA的肿瘤而不受sCEA竞争性抑制的独特机会，并将CEA / CD3-bscAb建立为一种有前途且有效的治疗方法。

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