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Abstract

Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7), with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hours. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared with 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (P < 0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (P < 0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression, and superior efficacy. 

Author information

Green DJ1,2, Frayo SL3, Lin Y3, Hamlin DK4, Fisher DR5, Frost SH3, Kenoyer AL3, Hylarides MD3, Gopal AK3,2, Gooley TA3, Orozco JJ3,2, Till BG3,2, O'Steen S3, Orcutt KD6, Wilbur DS4, Wittrup KD6,7, Press OW3,2.

1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. dgreen@fhcrc.org.

2Department of Medicine, University of Washington, Seattle, Washington.

3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

4Department of Radiation Oncology, University of Washington, Seattle, Washington.

5Dade Moeller Health Group, Richland, Washington.

6Department of Chemical Engineering, Massachusetts Institute of Technology, Boston, Massachusetts.

7Department of Biological Engineering, Massachusetts Institute of Technology, Boston, Massachusetts.