Research Project
9162480
Acute Myeloid Leukemia (AML) is an aggressive myeloid neoplasm characterized by rapid growth and invasion of ?20% of white blood cells that accumulate in blood and bone marrow and interfere with production of normal blood cells. The National Cancer Institute estimates that 18,860 new cases of AML will occur in 2014 with 10,460 resulting deaths. Although AML is a relatively rare disease with 1.1% of cancer deaths in the US, its incidence is expected to increase as population ages. Our understanding of AML?s biology has dramatically increased over the past two decades with 60-70% of adult patients expected to achieve complete remission following induction chemotherapy. However treatment of relapsed AML has been relatively ineffective, with remission rates from 20-50% and overall disease-free survival rates <10%. No standard regimen exists for relapsed AML patients thus the unmet need for better and safer therapies. We propose an innovative, more efficacious and safer delivery system that sequentially pre-targets CD123, a surface marker over-expressed by AML tumors, and specifically delivers high radionuclide payloads for PET imaging as surrogate for radioimmunotherapy. In vitro experiments and animal models were designed for proof-of-concept in Phase I as a prelude to IND-enabling studies in a Phase II proposal. In this application, we intend to demonstrate with in vitro and in vivo studies that we can achieve the following goals: (i) Synthesize the ADAPTTM-based Targeting Unit (ATU) and radionuclide-loaded Carrier Unit (ACU) necessary for the proposed in vitro and in vivo studies, as well as all positive and negative control reagents (SA1-2); (ii) Validate CD123 as an appropriate AML surface marker for targeting AML cells (SA3); (iii) Target efficiently and selectively AML cells with anti-CD123 antibodies (SA3); (iv) Deliver efficiently and selectively to the surface of AML cells a radionuclide payload that is subsequently internalized (SA3); (v) Establish in vivo the efficacy of the proposed CD123-targeted treatment at imaging AML cells via microPET with high sensitivity and high resolution as a proof-of-concept and surrogate for radioimmunotherapy (SA4); and (vi) Establish a preliminary in vivo safety profile for the proposed approach (SA4).
