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.
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