Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers.
Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers.
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DOI：
10.1158/0008-5472.can-16-0571
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发表时间：
2016-11-15
期刊：
影响因子：
11.2
通讯作者：
Press OW
中科院分区：
文献类型：
--
作者：
Green DJ;Frayo SL;Lin Y;Hamlin DK;Fisher DR;Frost SH;Kenoyer AL;Hylarides MD;Gopal AK;Gooley TA;Orozco JJ;Till BG;O'Steen S;Orcutt KD;Wilbur DS;Wittrup KD;Press OW
在非霍奇金淋巴瘤（NHL）中靶向CD 20的链霉亲和素（SA）-生物素预靶向放射免疫治疗（PRIT）在模型系统中表现出显著的疗效，但SA免疫原性和内源性生物素的干扰可能使该方法的临床转化复杂化。在这项研究中，我们设计了一种双特异性融合蛋白（FP），它避开了该系统所施加的限制。简而言之，FP的一个臂是抗人CD 20抗体（2 H7），FP的另一个臂是用于被非常高亲和力的抗Y-DOTA scFv抗体（C825）捕获的放射性标记的配体（钇[Y]-DOTA）的抗螯合放射性金属陷阱。在携带人淋巴瘤异种移植物的鼠受试者中比较SA-生物素和双特异性FP（2 H7-Fc-C825）PRIT的头对头生物分布实验证明了在24小时时每种模式的几乎相同的肿瘤靶向。然而，与2 H7-Fc-C825相比，1F 5-SA给药后血液和正常器官中的残留放射性始终较高。因此，对于2 H7-Fc-C825，肿瘤与正常组织的分布比率是上级的（p<0.0001）。在患有拉莫斯或Granta皮下淋巴瘤的受试者中的治疗研究证明，2 H7-Fc-C825 PRIT是高度有效的，并且骨髓抑制显著低于1F 5-SA（p<0.0001）。所有接受最佳剂量的2 H7-Fc-C825随后90 Y-DOTA的动物在150天内治愈，而对照动物中的肿瘤生长迅速进展，在25天内完全发病。除了证明免疫原性风险降低和不存在内源性生物素干扰外，我们的研究结果还提供了在未来临床试验中优选使用双特异性PRIT的临床前概念证明，因为其生物分布特征略上级，骨髓抑制较少和疗效上级。
Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7) with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hrs. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared to 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (p<0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (p<0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression and superior efficacy.