RT Journal Article SR Electronic T1 90Y-DOTA-hLL2: An Agent for Radioimmunotherapy of Non-Hodgkin’s Lymphoma JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 77 OP 84 VO 44 IS 1 A1 Gary L. Griffiths A1 Serengulam V. Govindan A1 Robert M. Sharkey A1 Darrell R. Fisher A1 David M. Goldenberg YR 2003 UL http://jnm.snmjournals.org/content/44/1/77.abstract AB The goal of this work was to determine an optimal radioimmunotherapy agent for further development against non-Hodgkin’s lymphoma. We sought to establish the stability profile of 90Y-labeled humanized LL2 (hLL2) monoclonal antibody (mAb) when prepared with different chelating agents and, from these data, to estimate the dosimetric improvement to be expected from use of the most stable 90Y-chelate-hLL2 complex. Methods: The complementarity-determining region–grafted (humanized) anti-CD22 mAb, hLL2 (epratuzumab), was conjugated to 3 different chelating agents, 2 of which were derivatives of diethylenetriaminepentaacetic acid (DTPA) and 1 of which was the macrocyclic chelate 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA). The 3 hLL2 conjugates were radiolabeled with 90Y and tested for stability in vitro against a 10,000-fold molar excess of free DTPA over 9 d. They were also tested against normal human serum at 37°C over 12 d. Each conjugate was radiolabeled with the γ-emitting radionuclide, 88Y, and compared for biodistribution in normal and lymphoma xenograft–bearing athymic mice. In vivo data were analyzed for statistical differences in the uptake of yttrium in bone and washed bone when either the DOTA or the Mx-DTPA chelates were used, and dosimetry calculations were made for each complex. Results: 90Y-DOTA complex of the hLL2 mAb was completely stable to either DTPA or serum challenge for the duration of either experiment (equivalent to 3.3–4.5 half-lives of 90Y radionuclide or >90% of possible 90Y decays from any initial starting activity). Complexes of hLL2 that had been prepared using the DTPA-type chelates lost 3%–4% of initially bound 90Y over the first few days and about 10%–15% over the duration of the challenges. In vivo, these stability differences manifested as significantly lower yttrium uptake in bone and cortical bone over a 10-d period when DOTA was used as the yttrium chelating agent. Absorbed doses per 37 MBq (1 mCi) of 90Y-mAb were 3,555 and 5,405 cGy for bone and 2,664 and 4,524 cGy for washed bone for 90Y-DOTA-hLL2 and 90Y-MxDTPA-hLL2, respectively, amounting to 52.0% and 69.8% increases in absorbed radiation doses for bone and washed bone, respectively, when a DOTA chelate was switched to a Mx-DTPA chelate. Conclusion: 90Y-hLL2 prepared with the DOTA chelate represents an improved agent for radioimmunotherapy of non-Hodgkin’s lymphoma, with an in vivo model demonstrating a large reduction in bone-deposited yttrium, compared with 90Y-hLL2 agents prepared with open-chain DTPA-type chelating agents. Dosimetry suggests that this benefit will result in a substantial toxicologic advantage for a DOTA-based hLL2 conjugate.