Potentially curative treatments for acute myeloid leukemia (AML) are limited to intensive systemic
chemotherapy with or without allogeneic bone marrow transplantation (BMT). However, not every patient is
healthy enough to tolerate intensive treatments, and not every patient may have a suitably HLA-matched stem
cell donor, especially patients from ethnic minority groups. Targeted agents have recently been approved to
treat AML, but these usually require intensive systemic chemotherapy to optimize efficacy. Furthermore, AML
is genetically heterogeneous with distinct genetic mutations and chromosomal alterations that makes targeted-
agent monotherapy unlikely to be curative. AML, like most hematologic malignancies, is very sensitive to
radiation therapy but even involved field radiation may be too toxic and ineffective for disseminated systemic
disease. However, radioimmunotherapy (RIT) mitigates the off-target toxicity by using monoclonal antibodies
conjugated to radioactive isotopes to deliver radiation payloads directly to sites of disease by virtue of the
antibody specificity. We have shown that RIT using 90Y- and 131I-radiolabeled anti-CD45 antibody targets
radiation to sites of leukemia while minimizing radiation to uninvolved organs. We have improved upon our
approach without increasing toxicity by targeting higher energy alpha-emitting radionuclides (astatine-211;
211At) to sites of disease and by developing a pre-targeted RIT (PRIT) approach using bispecific antibodies
targeting CD45 and 90Y-DOTA.
Using preclinical murine models, we now propose to identify synergistic combinations of 211At- and 90Y-anti-
CD45 RIT with novel targeted therapies that interfere with DNA repair or promote apoptosis. We will do this by
first assessing for synergy between alpha- or beta-emitting radionuclides (211At- and 90Y-) employed in anti-
CD45 directly labeled RIT with recently approved targeted agents (PARP and BCL2 inhibitors) in both
disseminated syngeneic and xenograft leukemia murine models. Second, we will improve therapeutic efficacy
of anti-CD45 PRIT via bispecific antibody constructs targeting CD45 and 90Y-DOTA by assessing for synergy
with targeted therapies (PARP and BCL2 inhibitors) in leukemia murine models. We will characterize the extent
of DNA damage achieved with these two approaches as a means to elucidate the mechanism of efficacy.
Finally, we will compare these two approaches as part of conditioning prior to allogeneic BMT using
haploidentical, or partially matched donors, as all patients should have haploidentical donors.
These preclinical studies should readily translate into clinical trials given our infrastructure for NIH funded and
pharmaceutical-sponsored clinical trials, using anti-CD45 RIT prior to bone marrow transplantation for
aggressive hematologic malignancies. These studies will add effective, well-tolerated treatment options for
patients with AML by identifying synergistic combinations of targeted agents with anti-CD45 RIT approaches
and by identifying the optimal RIT approach prior to haploidentical BMT.