Improved therapeutic results by pretargeted radioimmunotherapy of non-Hodgkin's lymphoma with a new recombinant, trivalent, anti-CD20, bispecific antibody.
Improved therapeutic results by pretargeted radioimmunotherapy of non-Hodgkin's lymphoma with a new recombinant, trivalent, anti-CD20, bispecific antibody.
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使用新型重组三价抗 CD20 双特异性抗体对非霍奇金淋巴瘤进行预靶向放射免疫治疗，改善了治疗效果。
DOI：
10.1158/0008-5472.can-08-0037
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发表时间：
2008
期刊：
影响因子：
11.2
通讯作者：
Goldenberg,DavidM
中科院分区：
文献类型：
--
作者：
Sharkey,RobertM;Karacay,Habibe;Litwin,Samuel;Rossi,EdmundA;McBride,WilliamJ;Chang,Chien-Hsing;Goldenberg,DavidM
我们研究了一种新的重组抗cd20双特异性抗体（bsMAb）的预靶向方法，与传统的90y -抗cd20 IgG和化学偶联的bsMAb相比，90y -1,4,7,10-四氮杂环十二烷-N，N ',N ',N ' -四乙酸（90Y-DOTA）肽是否可以降低血液学毒性并改善治疗效果。TF4是一种人源化的三Fab单抗，其中两个Fab结合CD20，一个Fab结合组胺-琥珀酰-甘氨酸（HSG），采用坞锁（DNL）方法，在Ramos b细胞淋巴瘤裸鼠中进行了检测。最佳预靶向需要TF4与90y - dota - hsg之间间隔29 h，并且TF4的摩尔数增加20倍。TF4比抗cd20 IgG更快地从血液中清除，并在肝脏、脾脏和肾脏中进行早期加工。24小时时，与抗cd20 Fab ×抗hsg Fab化学偶联物相比，TF4使肿瘤对111in - hsg肽的摄取提高2.6倍[13%对5%注射剂量/克（ID/g）]，使肿瘤与血液的比率提高45倍（770对17），与放射性标记的抗cd20 IgG相比，分别提高1.6倍（9.0%对5.6% ID/g）和1600倍（522对0.32）。在90y -抗cd20 IgG的最大剂量下，观察到严重（≥90%）和长期的白细胞减少，而预先靶向导致≤60%的短暂下降。TF4预靶向治疗显著提高了生存率，即使在相对较低的剂量下，也能治愈33%至90%的动物，而大多数肿瘤进展迅速，无法用90y -anti- cd20 IgG治愈。这些结果表明，与使用直接放射标记抗体或化学偶联bsMAb的常规治疗相比，使用dnl构建的tri-Fab， bsMAb进行预靶向放射免疫治疗（RAIT）的治疗指数有所提高。这些令人鼓舞的结果促使这些结构在患者中进行预先靶向RAIT的测试。[癌症研究2008；68 (13): 5282 - 90)
We examined whether a pretargeting method using a new recombinant anti-CD20 bispecific antibody (bsMAb) followed by90Y-1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (90Y-DOTA)-peptide could reduce hematologic toxicity yet improve therapeutic responses compared with conventional90Y-anti-CD20 IgG and a chemically conjugated bsMAb. TF4, a humanized, tri-Fab bsMAb with two Fabs binding CD20 and one Fab binding histamine-succinyl-glycine (HSG), developed by the dock and lock (DNL) method, was tested in nude mice with Ramos B-cell lymphomas. Optimal pretargeting required a 29-h interval between TF4 and90Y-DOTA-HSG, and 20-fold more moles of TF4. TF4 cleared more rapidly from the blood than anti-CD20 IgG, with early processing in the liver, spleen, and kidney. At 24 h, TF4 improved tumor uptake of111In-HSG-peptide 2.6-fold [13% versus 5% injected dose per gram (ID/g)] and enhanced tumor to blood ratios >45-fold (770 versus 17), compared with an anti-CD20 Fab × anti-HSG Fab chemical conjugate, and by 1.6-fold (9.0% versus 5.6% ID/g) and 1,600-fold (522 versus 0.32), respectively, compared with radiolabeled anti-CD20 IgG. A severe (≥90%) and prolonged reduction of WBCs was observed at the maximum dose of90Y-anti-CD20 IgG, whereas pretargeting resulted in a ≤60% transient drop. TF4 pretargeting resulted in highly significant improvement in survival, curing 33% to 90% of the animals, even at relatively low doses, whereas most tumors progressed quickly without cures with90Y-anti-CD20 IgG. These results indicate an improved therapeutic index with pretargeted radioimmunotherapy (RAIT) using a DNL-constructed tri-Fab, bsMAb, compared with conventional therapy with directly radiolabeled antibody or with a chemically conjugated bsMAb. These encouraging results prompt testing these constructs for pretargeting RAIT in patients. [Cancer Res 2008;68(13):5282–90]