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 (α-CD20) tumor-targeting component and an azide- and yttrium-90-(90Y) 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 α-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 α-CD20 and thus enhance the antitumor effects, as justified by comprehensive in vitro and in vivo studies in mouse NHL xenograft and disseminated models.
Bibliographical noteFunding Information:
We thank the Microscopy Service Laboratory Core, Animal Study Core, Small Animal Imaging Facility, Animal Clinical Laboratory, Animal Histopathology Core Facility, Translation Pathology Lab, UNC Flow Cytometry Core Facility, UNC Macromolecular Interactions Facility and UNC Michael Hooker Proteomics Centre in the School of Medicine, and Chapel Hill Analytical and Nanofabrication Laboratory (CHANL) at the University of North Carolina at Chapel Hill for their assistance with procedures in this manuscript. The UNC Flow Cytometry Core Facility, UNC Macromolecular Interactions Facility and UNC Michael Hooker Proteomics Center are supported in part by P30CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. Genentech, Inc (San Fransico, CA) is thanked for supplying rituximab and for permission to publish this work. This work was supported by the University Cancer Research Fund from the University of North Carolina and R01CA178748 (A.Z.W.) grant from the National Institutes of Health/National Cancer Institute. A.Z.W. was also supported by the National Institutes of Health Center for Nanotechnology Excellence Grant U54-CA151652.
This work was supported by the University Cancer Research Fund from the University of North Carolina and R01CA178748 (A.Z.W.) grant from the National Institutes of Health/National Cancer Institute. A.Z.W. was also supported by the National Institutes of Health Center for Nanotechnology Excellence Grant U54-CA151652.
© 2018 American Chemical Society.
All Science Journal Classification (ASJC) codes
- Materials Science(all)
- Physics and Astronomy(all)