Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers.

Autor:	Green DJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. dgreen@fhcrc.org.; Department of Medicine, University of Washington, Seattle, Washington., Frayo SL; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Lin Y; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Hamlin DK; Department of Radiation Oncology, University of Washington, Seattle, Washington., Fisher DR; Dade Moeller Health Group, Richland, Washington., Frost SH; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Kenoyer AL; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Hylarides MD; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Gopal AK; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington, Seattle, Washington., Gooley TA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Orozco JJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington, Seattle, Washington., Till BG; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington, Seattle, Washington., O'Steen S; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington., Orcutt KD; Department of Chemical Engineering, Massachusetts Institute of Technology, Boston, Massachusetts., Wilbur DS; Department of Radiation Oncology, University of Washington, Seattle, Washington., Wittrup KD; Department of Chemical Engineering, Massachusetts Institute of Technology, Boston, Massachusetts.; Department of Biological Engineering, Massachusetts Institute of Technology, Boston, Massachusetts., Press OW; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.; Department of Medicine, University of Washington, Seattle, Washington.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2016 Nov 15; Vol. 76 (22), pp. 6669-6679. Date of Electronic Publication: 2016 Sep 02.
DOI:	10.1158/0008-5472.CAN-16-0571
Abstrakt:	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 90 Y-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. Cancer Res; 76(22); 6669-79. ©2016 AACR. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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