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Preclinical evaluation of an 111In/225Ac theranostic targeting transformed MUC1 for triple negative breast cancer.
Theranostics ( IF 12.4 ) Pub Date : 2020-5-25 , DOI: 10.7150/thno.38236
Vanessa J Kelly 1 , Shu-Ta Wu 2, 3 , Vijay Gottumukkala 1 , Richard Coelho 1 , Keryn Palmer 1 , Surabhi Nair 1 , Timothy Erick 2 , Rahul Puri 3 , Ohad Ilovich 1 , Pinku Mukherjee 2, 3
Affiliation  

Rationale: Transformed MUC1 (tMUC1) is a cancer-associated antigen that is overexpressed in >90% of triple-negative breast cancers (TNBC), a highly metastatic and aggressive subtype of breast cancer. TAB004, a murine antibody targeting tMUC1, has shown efficacy for the targeted delivery of therapeutics to cancer cells. Our aim was to evaluate humanized TAB004 (hTAB004) as a potential theranostic for TNBC./nMethods: The internalization of hTAB004 in tMUC1 expressing HCC70 cells was assessed via fluorescent microscopy. hTAB004 was DOTA-conjugated and radiolabeled with Indium-111 or Actinium-225 and tested for stability and tMUC1 binding (ELISA, flow cytometry). Lastly, in vivo biodistribution (SPECT-CT), dosimetry, and efficacy of hTAB004 were evaluated using a TNBC orthotopic mouse model./nResults: hTAB004 was shown to bind and internalize into tMUC1-expressing cells. A production method of 225Ac-DOTA-hTAB004 (yield>97%, RCP>97% SA=5 kBq/µg) and 111In-DOTA-hTAB004 (yield>70%, RCP>99%, SA=884 kBq/µg) was developed. The labeled molecules retained their affinity to tMUC1 and were stable in formulation and mouse serum. In NSG female mice bearing orthotopic HCC70 xenografts, the in vivo tumor concentration of 111In-DOTA-hTAB004 was 65 ± 15 %ID/g (120 h post injection). A single 225Ac-DOTA-hTAB004 dose (18.5 kBq) caused a significant reduction in tumor volume (P<0.001, day 22) and increased survival compared to controls (P<0.007). The human dosimetry results were comparable to other clinically used agents./nConclusion: The results obtained with hTAB004 suggest that the 111In/225Ac-DOTA-hTAB004 combination has significant potential as a theranostic strategy in TNBC and merits further development toward clinical translation.

中文翻译:

对三联阴性乳腺癌的111In / 225Ac肿瘤治疗靶向转化MUC1的临床前评估。

原理:转化的MUC1(tMUC1)是一种与癌症相关的抗原,在90%以上的三阴性乳腺癌(TNBC)(一种高度转移和侵袭性乳腺癌亚型)中过表达。TAB004是一种靶向tMUC1的鼠抗体,已显示出将治疗药物靶向递送至癌细胞的功效。我们的目的是评估人源化TAB004(hTAB004)作为TNBC的潜在治疗方法。方法:通过荧光显微镜评估了表达tMUC1的HCC70细胞中hTAB004的内在化。将hTAB004与DOTA偶联并用Indium-111或Actinium-225进行放射性标记,并测试其稳定性和tMUC1结合(ELISA,流式细胞仪)。最后,体内使用TNBC原位小鼠模型评估了hTAB004的生物分布(SPECT-CT),剂量测定法和功效。/n结果:hTAB004已结合并内化到表达tMUC1的细胞中。的制造方法225的Ac-DOTA-hTAB004(产率> 97%,RCP> 97%SA = 5 KBQ /微克)和111的In-DOTA-hTAB004(产率> 70%,RCP> 99%,SA = 884 KBQ /微克)。标记的分子保留了对tMUC1的亲和力,并且在制剂和小鼠血清中稳定。在携带原位HCC70异种移植物的NSG雌性小鼠中,体内111 In-DOTA-hTAB004的肿瘤浓度为65±15%ID / g(注射后120 h)。单225与对照相比,Ac-DOTA-hTAB004剂量(18.5 kBq)导致肿瘤体积显着减少(P <0.001,第22天),并提高了生存率(P <0.007)。人类的剂量学结果堪比其他临床使用agents./n结论:与hTAB004得到的结果表明,111在/ 225 AC-DOTA-hTAB004组合有显著潜力在TNBC和案情向临床转化进一步发展的治疗诊断策略。
更新日期:2020-05-25
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