Conventional chemotherapy cures only 25-45% of patients with newly diagnosed acute myeloid leukemia (AML) and <5% of patients with relapsed AML. High dose chemoradiotherapy with allogeneic stem cell transplantation (SCT) improves the rates of cure to 50-60% for newly diagnosed AML and 20-30% for relapsed AML, however, it is clear that improved therapy is needed. Our group has previously documented the promise of incorporating radiolabeled anti- CD45 monoclonal antibodies (Ab) into SCT conditioning regimens for AML, but toxicity remains high and cure rates are still only 65% for newly diagnosed AML and <30% for relapsed AML using directly radiolabeled anti-hCD45 Ab and SCT. In this application, we investigate a novel approach to delivering radioimmunotherapy (RIT) for AML using a recombinant tetravalent single chain antibody-SA fusion protein, (scFv)4SA, directed against human hCD45, a dendrimeric N-acetylgalactosamine-containing """"""""clearing agent"""""""" and radiolabeled-DOTA-biotin. This multi-step anti- CD45 """"""""pretargeting"""""""" approach is hypothesized to amplify the amount of radiation delivered to AML cells, decrease the amount of radiation delivered to the liver, lungs, and other normal organs, and markedly attenuate infusion-related toxicities.
In Aim 1, we will investigate the pharmacokinetics and biodistributions of an anti-hCD45 (scFv)4SA fusion protein and radiobiotin in leukemia xenografts in athymic and SCID mouse models and will compare the biodistributions, toxicities, efficacies and dosimetries achieved with pretargeted RIT with those using conventional anti-CD45 RIT.
In Aim 2, we will compare the relative merits of conventional KIT and pretargeted RIT in a rigorous, syngeneic murine leukemia model using an Ab and an (scFv)4SA fusion protein directed against murine mCD45 using the approaches described in Aim 1.
In Aim 3, we will evaluate the safety, pharmacokinetics, and biodistributions of both the (scFv)4SA directed to hCD45 and the radiobiotin component in non-human primates (macaques), using serial quantitative gamma camera imaging, blood sampling, biopsies, radioautography, and necropsy.
In Aim 4, we will generate a Master Cell Bank for the anti-human CD45 (scFv)4SA fusion protein and produce, purify and characterize sufficient material to initiate Phase I & II clinical trials of the pretargeting approach in AML. We hypothesize that the pretargeting strategies defined in this proposal will improve the tumor-to-normal organ ratios of absorbed radiation compared with conventional RIT, allowing improvement in response rates and response durations with less toxicity than is currently feasible. We anticipate rapid translation of the results of these preclinical experiments into our clinical RIT program for human AML.
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