Amann Maria, Brischwein Klaus, Lutterbuese Petra, Parr Larissa, Petersen Laetitia, Lorenczewski Grit, Krinner Eva, Bruckmeier Sandra, Lippold Sandra, Kischel Roman, Lutterbuese Ralf, Kufer Peter, Baeuerle Patrick A, Schlereth Bernd
Micromet AG, Munich, Germany.
Cancer Res. 2008 Jan 1;68(1):143-51. doi: 10.1158/0008-5472.CAN-07-2182.
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 microg/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 microg/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.
上皮细胞黏附分子（EpCAM，即CD326）是已知的表达最为频繁且水平最高的肿瘤相关抗原之一，最近还在源自人乳腺、结肠、前列腺和胰腺肿瘤的癌症干细胞上被发现。然而，与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也在包括胰腺、结肠、肺、胆管和乳腺上皮在内的正常组织中表达。为了评估双特异性T细胞衔接器（BiTE）类的EpCAM/CD3双特异性单链抗体构建体的治疗窗口，我们从针对小鼠EpCAM和CD3抗原的单链抗体构建了MT110的小鼠替代物（muS110）。免疫组织化学分析表明，人与小鼠的多种组织上EpCAM蛋白的表达在分布和水平方面相似，仅存在细微差异。在同基因4T1原位乳腺癌和CT-26肺癌小鼠模型中，muS110低至5微克/千克时即表现出显著的抗肿瘤活性。通过动物体内剂量递增，连续数周给予高达400微克/千克的muS110仍可耐受，这表明小鼠体内存在针对EpCAM特异性BiTE抗体的显著治疗窗口。已发现muS110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。
