Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90 Y-DOTA
| Autor: | Oliver W. Press, Damian J. Green, K. Dane Wittrup, Shyril O'Steen, Kelly Davis Orcutt, Margaret E. Nartea, Ethan R. Balkin, Rosario Guel, Yukang Lin, Alexandra H. Hernandez, Aimee L. Kenoyer, Darrell R. Fisher, Brian G. Till, Brenda M. Sandmaier, Ajay K. Gopal, John M. Pagel, Mark D. Hylarides, Johnnie J. Orozco, D. Scott Wilbur, Donald K. Hamlin |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research biology business.industry Immunogenicity Myeloid leukemia Spleen medicine.disease 03 medical and health sciences Leukemia 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis biology.protein Percent Injected Dose medicine Cancer research Pretargeted Radioimmunotherapy Bone marrow Antibody business |
| Zdroj: | PMC |
| Popis: | 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 μCi) 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 ( |
| Databáze: | OpenAIRE |
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