Karacay Habibe, Sharkey Robert M, Gold David V, Ragland Dan R, McBride William J, Rossi Edmund A, Chang Chien-Hsing, Goldenberg David M
Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA.
J Nucl Med. 2009 Dec;50(12):2008-16. doi: 10.2967/jnumed.109.067686.
Pancreatic cancer is a silent disease that most commonly presents in an already metastatic form. Current treatment options provide little survival benefit. Radiolabeled PAM4 IgG, a monoclonal antibody that recognizes a unique epitope associated with a mucin found almost exclusively in pancreatic cancer, has shown encouraging therapeutic effects in animal models and in early clinical testing ((90)Y-humanized PAM4 IgG, (90)Y-clivatuzumab tetraxetan). The studies reported herein examine a new pretargeting procedure for delivering therapeutic radionuclides.
We prepared a humanized, recombinant tri-Fab bispecific monoclonal antibody (bsmAb) (TF10) using specificity for targeting pancreatic cancer of PAM4 and another Fab binding to a hapten (histamine-succinyl-glycine [HSG]) and tested this in a pretargeting setting with a (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-di-HSG-peptide (pretargeted radioimmunotherapy [PT-RAIT]). Nude mice bearing established Capan-1 human pancreatic cancer xenografts were given TF10 and then received the (90)Y peptide as a single bolus dose 19 h later, or the therapy cycle was fractionated weekly. Other studies examined different combinations with gemcitabine.
PT-RAIT of 18.5 MBq ( approximately 50% of its maximum tolerated dose [MTD]) was as effective as the MTD of (90)Y-PAM4 IgG (5.55 MBq). Three monthly doses of 9.25 MBq of PT-RAIT combined with a monthly cycle of gemcitabine (3 weekly, 6-mg doses) significantly enhanced survival, compared with PT-RAIT alone. Adding gemcitabine as a radiosensitizer to 9.25 MBq of PT-RAIT enhanced objective responses. Weekly fractionation of the PT-RAIT, as compared with a single treatment, improved responses.
PAM4-based PT-RAIT with (90)Y hapten peptide is an effective treatment for pancreatic cancer, with less toxicity than (90)Y-PAM4 IgG, in this model. Combinations with gemcitabine and dose fractionation of the PT-RAIT enhanced therapeutic responses.
胰腺癌是一种隐匿性疾病，最常见的表现形式是已经发生转移。目前的治疗方案对提高生存率作用甚微。放射性标记的PAM4 IgG是一种单克隆抗体，可识别一种几乎仅在胰腺癌中发现的与粘蛋白相关的独特表位，在动物模型和早期临床试验中已显示出令人鼓舞的治疗效果（（90）Y-人源化PAM4 IgG，（90）Y-克利伐单抗四乙酸盐）。本文报道的研究考察了一种用于递送治疗性放射性核素的新预靶向程序。
我们制备了一种人源化重组三价Fab双特异性单克隆抗体（bsmAb）（TF10），它利用PAM4对胰腺癌的靶向特异性以及另一个与半抗原（组胺-琥珀酰-甘氨酸[HSG]）结合的Fab，并在预靶向环境中用（90）Y-1,4,7,10-四氮杂环十二烷-N,N',N'',N'''-四乙酸-二-HSG-肽进行测试（预靶向放射免疫疗法[PT-RAIT]）。给患有已建立的Capan-1人胰腺癌异种移植瘤的裸鼠注射TF10，然后在19小时后给予（90）Y肽单次推注剂量，或者治疗周期每周进行分次给药。其他研究考察了与吉西他滨的不同联合用药。
18.5 MBq的PT-RAIT（约为其最大耐受剂量[MTD]的50%）与（90）Y-PAM4 IgG的MTD（5.55 MBq）效果相同。与单独使用PT-RAIT相比，每月三次给予9.25 MBq的PT-RAIT并联合每月一次的吉西他滨周期治疗（每周3次，每次6 mg剂量）显著提高了生存率。将吉西他滨作为放射增敏剂添加到9.25 MBq的PT-RAIT中可增强客观缓解率。与单次治疗相比，PT-RAIT每周分次给药可改善缓解情况。
在该模型中，基于PAM4的PT-RAIT联合（90）Y半抗原肽是一种有效的胰腺癌治疗方法，毒性比（90）Y-PAM4 IgG小。与吉西他滨联合以及PT-RAIT的剂量分割可增强治疗反应。
