Colorectal cancer represents the second most common cause of cancer-related death. The human A33 transmembrane glycoprotein is a validated tumor-associated antigen, expressed in 95% of primary and metastatic colorectal cancers. Using phage display technology, we generated a human monoclonal antibody (termed A2) specific to human A33 and we compared its epitope and performance to those of previously described clinical-stage anti-human A33 antibodies. All antibodies recognized a similar immunodominant epitope, located in the V-domain of A33, as revealed by SPOT analysis. The A2 antibody homogenously stained samples of poorly, moderately, and well differentiated colon adenocarcinomas. All antibodies also exhibited an intense staining of healthy human colon sections. The A2 antibody, reformatted in murine IgG2a format, preferentially localized to A33-transfected CT26 murine colon adenocarcinomas in immunocompetent mice with a homogenous distribution within the tumor mass, while other antibodies exhibited a patchy uptake in neoplastic lesions. A2 efficiently induced killing of A33-expressing cells through antibody-dependent cell-mediated cytotoxicity in vitro and was able to inhibit the growth of A33-positive murine CT26 and C51 lung metastases in vivo. Anti-A33 antibodies may thus represent useful vehicles for the selective delivery of bioactive payloads to colorectal cancer, or may be used in IgG format in a setting of minimal residual disease.

中文翻译：

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对A33糖蛋白具有特异性的新型人单克隆抗体可识别结直肠癌并抑制转移。

大肠癌代表与癌症相关的死亡的第二大最常见原因。人A33跨膜糖蛋白是一种经过验证的肿瘤相关抗原，在95％的原发性和转移性结直肠癌中表达。使用噬菌体展示技术，我们生成了对人A33特异的人单克隆抗体（称为A2），并将其表位和性能与先前描述的临床阶段抗人A33抗体进行了比较。如SPOT分析所示，所有抗体均识别位于A33 V域的类似免疫优势表位。A2抗体对低分化，中分化和高分化结肠腺癌的样品进行均质染色。所有抗体还表现出健康的人类结肠切片的强烈染色。重新格式化为鼠IgG2a格式的A2抗体，优先定位于免疫活性小鼠中经A33转染的CT26鼠结肠腺癌，并在肿瘤块内均匀分布，而其他抗体则在肿瘤性病变中表现出斑片状吸收。A2在体外通过抗体依赖性细胞介导的细胞毒性有效诱导了表达A33的细胞的杀伤，并且能够在体内抑制A33阳性鼠CT26和C51肺转移的生长。因此，抗A33抗体可以代表有用的载体，用于选择性地将生物活性有效载荷传递给结直肠癌，或者可以以IgG形式用于残留病最少的情况。A2在体外通过抗体依赖性细胞介导的细胞毒性有效诱导了表达A33的细胞的杀伤，并且能够在体内抑制A33阳性鼠CT26和C51肺转移的生长。因此，抗A33抗体可以代表有用的载体，用于选择性地将生物活性有效载荷传递给结直肠癌，或者可以以IgG形式用于残留病最少的情况。A2在体外通过抗体依赖性细胞介导的细胞毒性有效诱导了表达A33的细胞的杀伤，并且能够在体内抑制A33阳性鼠CT26和C51肺转移的生长。因此，抗A33抗体可以代表有用的载体，用于选择性地将生物活性有效载荷传递给结直肠癌，或者可以以IgG形式用于残留病最少的情况。