Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3
Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3
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DOI：
10.1158/0008-5472.can-07-2182
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发表时间：
2008-01-01
期刊：
影响因子：
11.2
通讯作者：
Schlereth, Bernd
中科院分区：
文献类型：
--
作者：
Amann, Maria;Brischwein, Klaus;Schlereth, Bernd
EPCAM(CD326)是已知的最常见和最高表达的肿瘤相关抗原之一，最近也在来自人类乳腺、结肠、前列腺和胰腺肿瘤的肿瘤干细胞上发现。然而，像许多其他用于基于抗体的免疫治疗方法的肿瘤相关抗原一样，EpCAM在正常组织中表达，包括胰腺、结肠、肺、胆管和乳腺的上皮细胞。为了评估EPCAM/CD3双特异性T细胞结合蛋白(BITE)类双特异性单链抗体构建的治疗窗口，我们从针对小鼠EpCAM和CD3抗原的单链抗体中构建了MT110的小鼠替代物(MuS110)。免疫组织化学分析表明，EpCAM蛋白在人和小鼠多种组织中的表达在分布和水平上是相似的，只是略有不同。在同基因4T1原位乳腺癌和CT-26肺癌小鼠模型中，MuS110均表现出显著的抗肿瘤活性，其最低剂量为5µg/kg。通过动物内剂量递增的方法将muS110的剂量增加到400微克/公斤，连续几周仍然可以耐受，这表明小鼠的EpCAM特异性咬合抗体存在一个重要的治疗窗口。MuS110被发现具有与MT110相似的体外特性和体内抗肿瘤活性，MT110是一种人EpCAM/人CD3双特异性BITE抗体，目前正处于正式的临床前开发阶段。
EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibody-based immunotherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens. Immunhistochemical analysis showed that, with minor differences, the expression of EpCAM protein on a large variety of tissues from man and mouse was similar with respect to distribution and level. MuS110 exhibited significant antitumor activity at as low as 5 mu g/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 mu g/kg by intraanimal dose escalation was still tolerated, indicating existence of a significant therapeutic window for an EpCAM-specific BiTE antibody in mice. MuS110 was found to have similar in vitro characteristics and in vivo antitumor activity as MT110, a human EpCAM/human CD3-bispecific BiTE antibody that currently is in formal preclinical development.