Establishment of 68Ga-DOTA-Based Pretargeted Radioimmunodiagnosis
Access to this document is restricted. Some items have been embargoed at the request of the author, but will be made publicly available after the "No Access Until" date.
During the embargo period, you may request access to the item by clicking the link to the restricted file(s) and completing the request form. If we have contact information for a Cornell author, we will contact the author and request permission to provide access. If we do not have contact information for a Cornell author, or the author denies or does not respond to our inquiry, we will not be able to provide access. For more information, review our policies for restricted content.
DOTA-radiometal (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) hapten complexes of β-emitters (177Lu or 90Y) and Œ±-emitters (225Ac) can be selectively targeted to tumors using an antitumor/anti-DOTA bispecific antibody (BsAb) approach in pretargeted radioimmunotherapy (DOTA-PRIT). Clinical translation of DOTA-PRIT may be accelerated by the development of a 68Ga companion diagnostic for PET imaging. Here, we report a novel radiohapten, which uses a 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) chelator for 68Ga labeling while retaining 175Lu in a benzyl-DOTA moiety for high-affinity antibody recognition (NODAGA-Pr; Pr = Proteus). Radiolabeling of NODAGA-Pr with 68Ga showed high radiochemical yield and purity, and in vitro studies confirmed high radiostability and negligible serum-protein binding. In vivo, using a DOTA-PRIT system targeting the GPA33 antigen in a human colorectal cancer mouse model, [68Ga]Ga-NODAGA-Pr demonstrated efficient tumor uptake and high-contrast PET imaging. Additional studies using an established DOTA-hapten test system‚îÄhuman embryonic kidney 293T cells expressing a transmembrane-anchored anti-DOTA scFv huC825 further confirmed its in vivo PRIT performance. These findings support [68Ga]Ga-NODAGA-Pr as a promising agent for pretargeted immunoPET and for imaging engineered cells expressing a radiohapten capture reporter gene, with favorable pharmacokinetics and tumor targeting well matched to existing therapeutic DOTA-radiohaptens.