Acute myelogenous leukemia (AML) currently kills the majority of afflicted patients despite treatment with combination chemotherapy and allogeneic stem cell transplantation (SCT). Radiolabeled anti- CD45 monoclonal antibodies (Ab) have been shown to improve outcomes for AML in the setting of SCT, but toxicity remains high and cure rates are suboptimal. The objective of this research proposal is to improve the cure rate of AML using radioimmunotherapy (RIT) targeting the CD45 cell antigen.
In Aim 1, we will compare the merits of conventional RIT using a directly radiolabeled anti-mCD45 Ab (30F11) with pretargeted RIT using a 30F11-streptavidin (SA) conjugate, followed by 131I, 177Lu or 90Y-labeled DOTA-biotin. Studies will be done in a syngeneic murine leukemia model (SJL/J) in which both AML cells and normal hematopoietic cells express mCD45.
In Aim 2, we will compare the in vivo biodistribution and radiation dosimetry of pretargeted ?-emitters (213Bi, 211At, 225Ac) with 2-emitting radionuclides in 4 different AML models. Two models target hCD45 on human AML cells (HEL) with a genetically engineered BC8 scFv4SA anti-hCD45 fusion protein that we eventually hope to use in clinical trials of pretargeted RIT. The other 2 models target mCD45 on murine AML cells in SJL/J mice with either minimal disease (2 days after injection of AML) or advanced disease (23 days after injection of AML) using an anti-mCD45 antibody-SA conjugate.
In Aim 3 we will compare the therapeutic efficacy of pretargeted ??emitting radionuclides with pretargeted ? emitting radioisotopes (213Bi 211At, 225Ac) in the 4 mouse models described in Aim 2.
In Aim 4 we will investigate combination therapy using cytotoxic chemotherapy with either pretargeted ?- or ?-emitting radionuclides, or both, in a disseminated model of AML. We hypothesize that the """"""""pretargeted"""""""" RIT strategies defined in this proposal will amplify the amount of radiation delivered to AML cells, decrease the radiation delivered to the liver, lungs, and other normal organs, improve remission and cure rates, prolong survival, and markedly attenuate toxicities compared to conventional RIT. We anticipate rapid translation of the results of these preclinical experiments into our clinical RIT program for AML.
Acute myelogenous leukemia (AML) develops in 13,290 Americans and kills 8,820 of them each year despite treatment with chemotherapy and stem cell transplantation. In this project, we plan to improve the cure rate of AML by targeting radionuclides to the CD45 antigen expressed on AML. Although this grant is specifically focused on AML, the treatment being developed can also be applied to other CD45-expressing malignancies, including other types of leukemia, myelodysplasia, and non-Hodgkin's lymphoma, that affect a total of more than 120,000 Americans each year.
|Orozco, Johnnie J; Kenoyer, Aimee; Balkin, Ethan R et al. (2016) Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment. Blood 127:352-9|
|Mawad, Raya; Becker, Pamela S; Hendrie, Paul et al. (2016) Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS. Br J Haematol 172:238-45|
|Frost, Sofia H L; Miller, Brian W; BÃ¤ck, Tom A et al. (2015) Î±-Imaging Confirmed Efficient Targeting of CD45-Positive Cells After 211At-Radioimmunotherapy for Hematopoietic Cell Transplantation. J Nucl Med 56:1766-73|
|Miller, Brian W; Frost, Sofia H L; Frayo, Shani L et al. (2015) Quantitative single-particle digital autoradiography with Î±-particle emitters for targeted radionuclide therapy using the iQID camera. Med Phys 42:4094-105|
|Frost, Sofia H L; Frayo, Shani L; Miller, Brian W et al. (2015) Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models. PLoS One 10:e0120561|
|Krem, Maxwell M; Press, Oliver W; Horwitz, Marshall S et al. (2015) Mechanisms and clinical applications of chromosomal instability in lymphoid malignancy. Br J Haematol 171:13-28|
|Larson, Steven M; Carrasquillo, Jorge A; Cheung, Nai-Kong V et al. (2015) Radioimmunotherapy of human tumours. Nat Rev Cancer 15:347-60|
|Orozco, Johnnie J; Balkin, Ethan R; Gooley, Ted A et al. (2014) Anti-CD45 radioimmunotherapy with 90Y but not 177Lu is effective treatment in a syngeneic murine leukemia model. PLoS One 9:e113601|
|Palanca-Wessels, Maria Corinna; Press, Oliver W (2014) Advances in the treatment of hematologic malignancies using immunoconjugates. Blood 123:2293-301|
|Balkin, Ethan R; Kenoyer, Aimee; Orozco, Johnnie J et al. (2014) In vivo localization of â¹â°Y and Â¹â·â·Lu radioimmunoconjugates using Cerenkov luminescence imaging in a disseminated murine leukemia model. Cancer Res 74:5846-54|
Showing the most recent 10 out of 30 publications