Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas

Abstract

Radiolabeled anti-CD20 antibodies produce responses in 60% to 95% of patients with relapsed non-Hodgkin lymphoma (NHL); however, absorbed radiation ratios between tumors and normal organs are relatively low, and many patients have relapses. In this study we compared the abilities of anti-CD45 (BC8) and anti-CD20 (1F5) antibodies to target human Ramos lymphoma xenografts in athymic mice. When direct radioiodination was performed with conventional methods, BC8 delivered 2-to 4-fold more radioiodine to tumors than 1F5, with tumor-to-normal organ ratios as high as 20:1 using radiolabeled BC8 compared with a maximal ratio of 9.8:1 using radioiodinated 1F5. To optimize the biodistribution of radioactivity, we performed studies following a pretargeting method using streptavidin (SA)-conjugated BC8 and 1F5. Injection of a synthetic clearing agent decreased the circulating level of conjugates by 80% to 90% within 1 hour. Pretargeting with BC8-SA resulted in a 2-to 4-fold greater tumor uptake of radiolabeled biotin than with 1F5-SA, with maximal tumor-to-normal organ ratios of more than 80:1 and approximately 16:1, respectively. Therapy experiments demonstrated that 400 Ci (14.8 MBq) or more of yttrium-90-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin cured 100% of mice treated with BC8-SA and more than 90% of mice pretargeted with 1F5-SA, with complete remission occurring 8 to 10 days sooner in mice receiving BC8-SA. After treatment with 200 Ci (7.4 MBq) 90 Y-DOTA-biotin, 70% of the mice treated with BC8-SA were cured, but no mice were cured using 1F5-SA. Doses up to 800 Ci (29.6 MBq) 90 Y-DOTA-biotin were delivered with minor toxicity using either antibody conjugate. These lymphoma xenograft data suggest that pretargeted radioimmunotherapy using either anti-CD20 or anti-CD45 conjugates is highly effective and minimally toxic. (Blood.

Anti-CD45 radioimmunotherapy using 211At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model

“…Because radioiodine has been reproducibly used in prior biodistribution studies, 20,25 we labeled B10-30F11 with 125 I and 211 At for comparison. Uptake of 125 I-B10-30F11 in the spleen was 67.6% 6 8% ID/g by 8 hours, and 24 hours after injection of 125 I-B10-30F11, the spleen retained more activity (42.3% 6 8% ID/g) than any other tissue at this same time point ( Figure 1A).…”

“…All toxicity tests were performed by Phoenix Central Laboratory (Everett, WA). 25 Values were compared with those obtained at the same time points from untreated age-matched control SJL/J mice. …”

Pretargeted Radioimmunotherapy for B-Cell Lymphomas

“…The biotin molecule on the clearing agent does not affect the binding kinetics of this small-molecule radionuclide, as the clearing agent biotin has an affinity for streptavidin that is one-one thousandth that of the radiobiotin in the treatment step (17). Clearing agent therefore neither blocks the binding of the DOTA-conjugated radionuclide nor is capable of stripping antibody bound to tumor from its target (13,18,19).…”

Structure-based design and synthesis of a bivalent iminobiotin analog showing strong affinity toward a low immunogenic streptavidin mutant

“…One possible use is in a pre-targeting system, conjugated with a monoclonal antibody. [7][8][9][10][11][12][13][14][15] In this pre-targeting application, a monoclonal antibody-SA conjugate is first injected into a patient and allowed to localize at the tumor. The excess reagent is then cleared and the biotinylated radiation carriers are administered.…”