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⁹⁰Y-DOTA-hLL2: An Agent for Radioimmunotherapy of Non-Hodgkin’s Lymphoma

¹ Immunomedics, Incorporated, Morris Plains, New Jersey
² Garden State Cancer Center, Belleville, New Jersey
³ Pacific Northwest National Laboratory, Richland, Washington

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 -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.

Key Words: CD22 • dosimetry • DOTA • humanized LL2 • ⁹⁰Y

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