De Jager R, Abdel-Nabi H, Serafini A, Pecking A, Klein J L, Hanna M G
Organon Teknika/Biotechnology Research Institute, Rockville, MD 20850-4373.
Semin Nucl Med. 1993 Apr;23(2):165-79. doi: 10.1016/s0001-2998(05)80096-0.
The use of radiolabeled murine monoclonal antibodies (MoAbs) for cancer immunodetection has been limited by the development of human antimouse antibodies (HAMA). Human monoclonal antibodies do not elicit a significant human antihuman (HAHA) response. The generation and production of human monoclonal antibodies met with technical difficulties that resulted in delaying their clinical testing. Human monoclonal antibodies of all isotypes have been obtained. Most were immunoglobulin (Ig) M directed against intracellular antigens. Two antibodies, 16.88 (IgM) and 88BV59 (IgG3k), recognize different epitopes on a tumor-associated antigen, CTA 16.88, homologous to cytokeratins 8, 18, and 19. CTA 16.88 is expressed by most epithelial-derived tumors including carcinomas of the colon, pancreas, breast, ovary, and lung. The in vivo targeting by these antibodies is related to their localization in nonnecrotic areas of tumors. Repeated administration of 16.88 over 5 weeks to a cumulative dose of 1,000 mg did not elicit a HAHA response. Two of 53 patients developed a low titer of HAHA 1 to 3 months after a single administration of 88BV59. Planar imaging of colorectal cancer with Iodine-131 (131I)-16.88 was positive in two studies in 9 of 12 and 16 of 20 patients preselected by immunohistochemistry. Tumors less than 2 cm in diameter are usually not detected. The lack of immunogenicity and long tumor residence time (average = 17 days) makes 16.88 a good candidate for therapy. Radioimmunlymphoscintigraphy with indium-111 (111In)-LiLo-16.88 administered by an intramammary route was used in the presurgical staging of primary breast cancer. The negative predictive value of lymph node metastases for tumors less than 3 cm was 90.5%. Planar and single photon emission computed tomography imaging of colorectal carcinoma with technetium-99m (99mTc) 88BV59 was compared with computed tomography (CT) scan in 36 surgical patients. The antibody scan was more sensitive than the CT scan in detecting abdominal and pelvic tumors: 68% versus 40% (P < .05). The combination of antibody scan and CT scan was superior to CT scan alone: 80% versus 40% (P < .01). Lesions as small as 0.5 cm in diameter were detected by antibody scan. The CT scan appears superior to the antibody scan for liver metastases. Patients with a high serum titer of HAMA from previous exposure to murine antibodies were successfully imaged. Antibody scans obtained with 99mTc-88BV59 have imaging characteristics similar to murine antibody scans obtained with radiolabeled IgGs. The absence or weak immunogenicity of the human monoclonal antibodies makes them good candidates for radioimmunodetection and radioimmunotherapy.
放射性标记的鼠单克隆抗体（MoAbs）用于癌症免疫检测受到人抗鼠抗体（HAMA）产生的限制。人单克隆抗体不会引发显著的人抗人（HAHA）反应。人单克隆抗体的产生和生产遇到技术难题，导致其临床试验延迟。已获得所有同种型的人单克隆抗体。大多数是针对细胞内抗原的免疫球蛋白（Ig）M。两种抗体，16.88（IgM）和88BV59（IgG3k），识别肿瘤相关抗原CTA 16.88上不同的表位，CTA 16.88与细胞角蛋白8、18和19同源。CTA 16.88在大多数上皮来源的肿瘤中表达，包括结肠癌、胰腺癌、乳腺癌、卵巢癌和肺癌。这些抗体在体内的靶向作用与其在肿瘤非坏死区域的定位有关。在5周内重复给予16.88，累积剂量达1000mg未引发HAHA反应。53例患者中有2例在单次给予88BV59后1至3个月出现低滴度的HAHA。在两项研究中，通过免疫组织化学预先选择的12例患者中有9例、20例患者中有16例，用碘-131（131I）-16.88对结直肠癌进行平面显像呈阳性。直径小于2cm的肿瘤通常未被检测到。16.88缺乏免疫原性且在肿瘤内停留时间长（平均=17天），使其成为良好的治疗候选药物。通过乳腺内途径给予铟-111（111In）-LiLo-16.88进行放射免疫淋巴闪烁显像用于原发性乳腺癌的术前分期。对于直径小于3cm的肿瘤，淋巴结转移的阴性预测值为90.5%。在36例手术患者中，将用锝-99m（99mTc）88BV59对结直肠癌进行的平面和单光子发射计算机断层显像与计算机断层扫描（CT）进行比较。抗体扫描在检测腹部和盆腔肿瘤方面比CT扫描更敏感：分别为68%和40%（P<0.05）。抗体扫描与CT扫描联合优于单独的CT扫描：分别为80%和40%（P<0.01）。抗体扫描可检测到直径小至0.5cm的病变。对于肝转移，CT扫描似乎优于抗体扫描。先前接触过鼠抗体而血清HAMA滴度高的患者成功进行了显像。用99mTc-88BV59获得的抗体扫描图像特征与用放射性标记IgG获得的鼠抗体扫描图像相似。人单克隆抗体缺乏或免疫原性弱，使其成为放射免疫检测和放射免疫治疗的良好候选药物。
