Bespoke Pretargeted Nanoradioimmunotherapy for the Treatment of Non-Hodgkin Lymphoma

被引:44
作者
Au, Kin Man [1 ,2 ,7 ]
Tripathy, Ashutosh [3 ]
Lin, Carolina Pe-I [4 ]
Wagner, Kyle [1 ,2 ,7 ]
Hong, Seungpyo [5 ]
Wang, Andrew Z. [1 ,2 ,7 ]
Park, Steven I. [6 ,7 ]
机构
[1] Univ N Carolina, Carolina Ctr Canc Nanotechnol Excellence, Carolina Inst Nanomed, Lab Nano & Translat Med, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Radiat Oncol, Chapel Hill, NC 27599 USA
[3] UNC Marcomol Interact Facil, Dept Biochem & Biophys, 1124 Genome Sci Bldg,250 Bell Tower Dr, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA
[5] Univ Wisconsin, Sch Pharm, 777 Highland Ave, Madison, WI 53705 USA
[6] Carolinas Hlth Care Syst, Levine Canc Inst, Div Hematol & Oncol, 100 Med Pk Dr,Suite 110, Concord, NC 28025 USA
[7] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
基金
美国国家卫生研究院;
关键词
non-Hodgkin lymphoma; pretargeted radioimmunotherapy; antibody; dendrimer; bioorthogonal ligation reaction; MONOCLONAL-ANTIBODY; ELDERLY-PATIENTS; RADIOIMMUNOTHERAPY; RITUXIMAB; CANCER; MECHANISMS; THERAPY; CELLS; MODEL; CD20;
D O I
10.1021/acsnano.7b08122
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Non-Hodgkin lymphoma (NHL) is one of the most common types of hematologic malignancies. Pretargeted radioimmunotherapy (PRIT), the sequential administration of a bispecific antibody-based primary tumor-targeting component followed by a radionucleotide-labeled treatment effector, has been developed to improve the treatment efficacy and to reduce the side effects of conventional RIT. Despite the preclinical success of PRIT, clinical trials revealed that the immunogenicity of the bispecific antibody as well as the presence of competing endogenous effector molecules often compromised the treatment. One strategy to improve PRIT is to utilize bio-orthogonal ligation reactions to minimize immunogenicity and improve targeting. Herein, we report a translatable pretargeted nanoradioimmunotherapy strategy for the treatment of NHL. This pretargeting system is composed of a dibenzylcyclooctyne (DBCO)-functionalized anti-CD20 antibody (alpha-CD20) tumor-targeting component and an azide- and yttrium-90-(Y-90) dual-functionalized dendrimer. The physicochemical properties of both pretargeting components have been extensively studied. We demonstrated that an optimized dual-functionalized dendrimer can undergo rapid strain-promoted azide-alkyne cycloaddition with the DBCO-functionalized alpha-CD20 at the physiological conditions. The treatment effector in our pretargeting system can not only selectively deliver radionucleotides to the target tumor cells but also increase the complement-dependent cytotoxicity of alpha-CD20 and thus enhance the antitumor effects, as justified by comprehensive in vitro and in vivo studies in mouse NHL xenograft and disseminated models.
引用
收藏
页码:1544 / 1563
页数:39
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