Chemical Modifications Of Antibodies For Tumor Targeting

肿瘤靶向抗体的化学修饰

• 批准号: 7733556
• 负责人: Chang Hum Paik
• 金额: $ 5万
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733556
• 关键词: 90Y; Antibodies; Antigens; Area Under Curve; Binding; Binding Sites; Blood Vessels; Body Weight; Caliber; Chemicals; Combined Modality Therapy; Coupled; Daclizumab; Daily; Dose; Enhancing Antibodies; Exposure to; Focused Ultrasound Therapy; Goals; Growth; Growth Factor; Hematologic Neoplasms; Human; I131 isotope; Image; Immune response; Immunoglobulin Fragments; Implant; Indium-111; Kinetics; Label; Maximum Tolerated Dose; Measures; Methods; Modification; Monoclonal Antibodies; Monoclonal Antibody CD20; Mus; Nude Mice; Optics; Paclitaxel; Patients; Physiologic pulse; Play; Pulse taking; Radiation; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Radiolabeled; Reporting; Research; Right-On; Role; Site; Solid Neoplasm; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Tumor Antibodies; Tumor Volume; United States Food and Drug Administration; United States National Institutes of Health; Upper arm; Week; Y 90 Ibritumomab Tiuxetan; cancer cell; cancer therapy; cell growth; day; fluorophore; imaging probe; improved; interstitial; iodine-131-tositumomab; mouse model; neoplastic cell; prevent; radiotracer; response; size; success; tumor; tumor growth; uptake

We previously reported that pulsed high intensity focused ultrasound (p-HIFU) treatment of LewisY antigen-expressing A431 tumor implanted in nude mice shortened the peak tumor uptake time (24 vs 48 hr for the control) and increased the peak tumor uptake value (38 vs 25% ID/g for the control) of In-111-labeled B3, a monoclonal antibody directed against LewisY antigen. The HIFU effect on enhancing tumor uptake was greater at earlier times up to 24 hr, but the effect was gradually diminished thereafter. The area-under-curve (AUC) calculations for the 120 hr period of the study indicated that a single pulsed-HIFU treatment could increase the radiation exposure dose of the radiolabeled antibody to tumors by 36%, compared to untreated control tumors (J Nucl Med 2008;49:295). Objectives: The goals of the research in the past year were to investigate if pulsed high intensity focused ultrasound (p-HIFU) exposures could increase the therapeutic efficacy of Y-90-labeled B3 alone and its combination with taxol. Groups of nude mice (n = 5-9 mice/group) were inoculated s.c. with A431 tumor cells expressing the LewisY antigen on the right hind flank. When the tumor size was 200 cubic mm, the mice received i.v. Y-90-labeled B3 alone (60 micro-Ci/150 micro-g B3 or 100 micro-Ci /150 micro-g B3), i.p. taxol alone (40 micro-g /Kg), the two agents together (Y-90-labeled B3 and after 24 hr, taxol), or no treatment. To investigate the effect of p-HIFU, the tumor was treated first with pulsed-HIFU, and within 10 min after p-HIFU, the mice received i.v. Y-90-labeled B3 with or without taxol. The tumor volume and the body weight were measured daily for the first 7 days and thereafter, two or three times a week. Mice were euthanized when the tumor size was 2 cm in diameter. Results: The tumors in the control mice without treatment grew rapidly with a median survival time of < 6 days. The taxol treatment stabilized the tumor growth for 5 days and thereafter, the tumors started re-growing with a median duration of survival of 16 days. The Y-90-labeled B3 treatment showed a dose-dependent response with a median survival time of 18 days for the 60 micro-Ci/150 micro-g B3 group and 21 days for the 100 micro-Ci /150 micro-g B3 group. The combination therapy with 60 micro-Ci/150 micro-g B3 plus taxol and 100 micro-Ci /150 micro-g B3 plus taxol showed a synergistic effect in reduction of tumor volume and prolongation of the survival time; 40% of tumors treated with 60 micro-Ci/150 micro-g B3 plus taxol completely disappeared by day 24 whereas by that time 70% of tumors treated with 100 micro-Ci /150 micro-g B3 plus taxol completely disappeared. The p-HIFU coupled with 60 micro-Ci/150 micro-g B3 treatment showed an additive effect in delaying the tumor growth with the median survival time comparable to the group treated with 100 micro-Ci /150 micro-g of Y-90 B3 without p-HIFU treatment. The p-HIFU treatment combined with 60 micro-Ci/150 micro-g B3 plus taxol treatment also showed an additive effect in delaying the tumor growth compared to the combination therapy without p-HIFU during the first 8 day period, thereafter the growth inhibition curve became almost superimposed with that of the combination therapy without p-HIFU. However, on day 21, the two curves started to diverge; the mean volume of tumors untreated with p-HIFU started to increase , whereas the mean volume of tumors treated with p-HIFU continued to decrease for 4 more days before the mean volume started to increase. Conclusion: In the nude mouse model of human epidermoid A431 tumor, the combination therapy of the Y-90-B3 with taxol showed a synergistic effect. The p-HIFU treatment provided an additive effect to the Y-90-B3 treatment alone as well as in the combination therapy of the Y-90-B3 with taxol. This additive effect appears to be due to the delivery enhancement of Y-90-B3 to the tumor sites. The additive effect of p-HIFU treatment to the synergistic combination therapy of Y-90-B3 and taxol appears to increase the efficacy of the combination therapy at a Y-90 B3 dose (60 micro-Ci) equivalent to 25% of the maximum tolerated dose (200-300 micro-Ci) and a clinically achievable taxol dose (40 mico-g/Kg). These findings are very encouraging and warrant further studies on this additive p-HIFU effect as well as the synergistic effect of the combination therapy.

我们以前报道过，脉冲高强度聚焦超声（p-HIFU）治疗的Lewis Y抗原表达的A431肿瘤移植在裸鼠中缩短了峰值肿瘤摄取时间（24与48小时的对照），并增加了峰值肿瘤摄取值（38与25% ID/g的对照）的In-111标记的B3，一种单克隆抗体直接针对Lewis Y抗原。HIFU增强肿瘤摄取的效果在24小时内的早期更大，但此后效果逐渐减弱。该研究的120小时时间段的曲线下面积（AUC）计算表明，与未处理的对照肿瘤相比，单次脉冲HIFU处理可以将放射性标记的抗体对肿瘤的辐射暴露剂量增加36%（J Nucl Med 2008;49：295）。目的：过去一年的研究目标是调查脉冲高强度聚焦超声（p-HIFU）暴露是否可以增加Y-90标记的B3单独及其与紫杉醇组合的治疗效果。将裸鼠组（n = 5-9只小鼠/组）皮下接种于小鼠皮下。在右后胁上具有表达LewisY抗原的A431肿瘤细胞。当肿瘤大小为200立方mm时，小鼠接受静脉内单独的Y-90标记的B3（60微Ci/150微g B3或100微Ci/150微g B3）、腹膜内单独的紫杉醇（40微g/Kg）、两种药剂一起（Y-90标记的B3和24小时后的紫杉醇）或不治疗。为了研究p-HIFU的效果，首先用脉冲HIFU治疗肿瘤，并且在p-HIFU后10分钟内，小鼠静脉内接受Y-90标记的B3（含或不含紫杉醇）。前7天每天测量肿瘤体积和体重，此后每周测量两次或三次。当肿瘤大小为直径2cm时，将小鼠安乐死。结果：未经治疗的对照小鼠的肿瘤生长迅速，中位生存时间< 6天。紫杉醇治疗使肿瘤生长稳定5天，此后，肿瘤开始重新生长，中位生存期为16天。Y-90标记的B3治疗显示出剂量依赖性反应，60 micro-Ci/150 micro-g B3组的中位存活时间为18天，100 micro-Ci /150 micro-g B3组为21天。60 μ Ci/150 μ g B_3加紫杉醇和100 μ Ci/150 μ g B_3加紫杉醇联合治疗在缩小肿瘤体积和延长生存期方面有协同作用;用60 μ Ci/150 μ g B3加紫杉醇治疗的肿瘤中，40%在第24天完全消失，而到那时，70%的肿瘤完全消失。用100 μ Ci/150 μ g B3加紫杉醇治疗的肿瘤完全消失。p-HIFU联合60 micro-Ci/150 micro-g B3治疗显示出延迟肿瘤生长的累加效应，中位生存时间与用100 micro-Ci /150 micro-g Y-90 B3治疗而不进行p-HIFU治疗的组相当。p-HIFU治疗与60 micro-Ci/150 micro-g B3加紫杉醇治疗的组合在前8天期间与没有p-HIFU的组合治疗相比也显示出延迟肿瘤生长的累加效应，此后生长抑制曲线变得几乎与没有p-HIFU的组合治疗的生长抑制曲线重叠。然而，在第21天，两条曲线开始发散;未用p-HIFU治疗的肿瘤的平均体积开始增加，而用p-HIFU治疗的肿瘤的平均体积在平均体积开始增加之前继续减少4天。结论：Y-90-B3与紫杉醇联合应用对裸鼠人表皮样A431肿瘤具有协同治疗作用。p-HIFU治疗为单独的Y-90-B3治疗以及Y-90-B3与紫杉醇的联合治疗提供了累加效应。这种累加效应似乎是由于Y-90-B3向肿瘤部位的递送增强。 p-HIFU治疗对Y-90-B3和紫杉醇的协同组合疗法的加和效应似乎增加了Y-90 B3剂量（60微Ci）（相当于最大耐受剂量（200-300微Ci）的25%）和临床可实现的紫杉醇剂量（40微g/Kg）下的组合疗法的功效。这些发现是非常令人鼓舞的，并保证进一步研究这种加性p-HIFU效应以及联合治疗的协同效应。

项目成果

Comparative cellular catabolism and retention of astatine-, bismuth-, and lead-radiolabeled internalizing monoclonal antibody.

比较细胞分解代谢和砹、铋和铅放射性标记内化单克隆抗体的保留。

• 发表时间: 2001
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Yao,Z;Garmestani,K;Wong,KJ;Park,LS;Dadachova,E;Yordanov,A;Waldmann,TA;Eckelman,WC;Paik,CH;Carrasquillo,JA
• 通讯作者: Carrasquillo,JA

Pharmacokinetics of 111In- and 125I-labeled antiTac single-chain Fv recombinant immunotoxin.

111In 和 125I 标记的 antiTac 单链 Fv 重组免疫毒素的药代动力学。

• 发表时间: 2000
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Kobayashi,H;Kao,CH;Kreitman,RJ;Le,N;Kim,MK;Brechbiel,MW;Paik,CH;Pastan,I;Carrasquillo,JA
• 通讯作者: Carrasquillo,JA

Imaging and phase I study of 111In- and 90Y-labeled anti-LewisY monoclonal antibody B3.

111In 和 90Y 标记的抗 LewisY 单克隆抗体 B3 的成像和 I 期研究。

• 发表时间: 2000
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Pai-Scherf,LH;Carrasquillo,JA;Paik,C;Gansow,O;Whatley,M;Pearson,D;Webber,K;Hamilton,M;Allegra,C;Brechbiel,M;Willingham,MC;Pastan,I
• 通讯作者: Pastan,I

In vitro and in vivo characterization of 67Ga(3+) complexes with cis,cis-1,3,5-triamino-cyclohexane-N,N',N"-triacetic acid derivatives.

67Ga(3) 与顺式,顺式-1,3,5-三氨基-环己烷-N,N,N"-三乙酸衍生物配合物的体外和体内表征。

• DOI: 10.1016/s0969-8051(01)00227-x
• 发表时间: 2001
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Dadachova,E;Park,C;Eberly,N;Ma,D;Paik,CH;Brechbiel,MW
• 通讯作者: Brechbiel,MW

Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15.

白介素 2 和 15 之间生物分布、药代动力学和肿瘤靶向的差异。

• 发表时间: 2000
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Kobayashi,H;Carrasquillo,JA;Paik,CH;Waldmann,TA;Tagaya,Y
• 通讯作者: Tagaya,Y