Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90Y-DOTA.
Molecular cancer therapeutics
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 (Ab)-streptavidin (SA) conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine and anti-human CD45 bispecific antibody (Ab) constructs using 30F11 and BC8 Ab, 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 (1200 µCi) of 90Y-DOTA-biotin survived at least 170 days after therapy, while all non-treated controls required euthanasia due to 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 µCi) of 90Y-DOTA-biotin had a survival advantage compared to untreated leukemic mice (median 43 versus 30 days, respectively, p<0.0001). These data suggest bispecific Ab mediated PRIT may be highly effective for leukemia therapy and translation to human studies.
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; Hamlin, Donald K; Wilbur, D Scott; Orcutt, Kelly D; Wittrup, K Dane; Green, Damian J; Gopal, Ajay K; Till, Brian G; Sandmaier, Brenda; Press, Oliver W; and Pagel, John M, "Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90Y-DOTA." (2020). Articles, Abstracts, and Reports. 3805.