Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90 Y-DOTA
Name
nihms-1635294.pdf
Description
Accepted version
Size
1.02 MB
Format
Adobe PDF
Checksum (MD5)
0a341ef7e1e2928babbe8c8ff7c5a4ce
Author(s)
Orozco, Johnnie J
Kenoyer, Aimee L
Lin, Yukang
O'Steen, Shyril
Guel, Rosario
Nartea, Margaret E
Hernandez, Alexandra H
Hylarides, Mark D
Fisher, Darrell R
Balkin, Ethan R
Date Issued
2020
Journal
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Version
Author's final manuscript
Abstract
© 2020 American Association for Cancer Research. Pretargeted radioimmunotherapy (PRIT) has been investigated as a multi-step approach to decrease relapse and toxicity for high-risk acute myeloid leukemia (AML). Relevant factors including endogenous biotin and immunogenicity, however, have limited the use of PRIT with an anti-CD45 antibody streptavidin conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine and anti-human CD45 bispecific antibody constructs using 30F11 and BC8 antibodies, respectively, combined with an anti-yttrium (Y)-DOTA single-chain variable fragment (C825) to capture a radiolabeled ligand. The bispecific construct targeting human CD45 (BC8-Fc-C825) had high uptake in leukemia HEL xenografts [7.8 = 0.02% percent injected dose/gram of tissue (% ID/g)]. Therapy studies showed that 70% of mice with HEL human xenografts treated with BC8-Fc-C825 followed by 44.4 MBq (1,200 mCi) of 90Y-DOTA-biotin survived at least 170 days after therapy, while all nontreated controls required euthanasia because of tumor progression by day 32. High uptake at sites of leukemia (spleen and bone marrow) was also seen with 30F11-IgG1-C825 in a syngeneic disseminated SJL murine leukemia model (spleen, 9.0 = 1.5% ID/g and bone marrow, 8.1 = 1.2% ID/g), with minimal uptake in all other normal organs (<0.5% ID/g) at 24 hours after 90Y-DOTA injections. SJL leukemia mice treated with the bispecific 30F11-IgG1-C825 and 29.6 MBq (800 mCi) of 90Y-DOTA-biotin had a survival advantage compared with untreated leukemic mice (median, 43 vs. 30 days, respectively; P < 0.0001). These data suggest bispecific antibody–mediated PRIT may be highly effective for leukemia therapy and translation to human studies.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1158/1535-7163.MCT-20-0306
