Sunday, November 24, 2024
11/24/2024
DESCRIPTION (provided by applicant): Most patients with acute myeloid leukemia (AML) relapse and die with chemotherapy resistant disease. With 7,000 deaths per year in the U.S. due to AML, novel agents which kill multi-drug resistant blasts are needed. Our laboratory has focused on the treatment of such patients with diphtheria fusion proteins. These molecules consist of the catalytic and translocation domains of diphtheria toxin (DT388) fused to leukemic blast selective ligands. We initially prepared DT388GMCSF by linking DT388 to human granulocyte-macrophage colony stimulating factor (GMCSF). In an ongoing clinical trial in refractory AML patients, remissions have been observed. However, side effects related to DT388GMCSF binding and inducing cytokine release from patient monocytes have occurred, necessitating steroid and antibiotic prophylaxis. Further, some patients failed to show leukemic cytoreductions. To improve the effectiveness and reduce toxicity, we synthesized a second generation fusion protein, DT388IL3, consisting of DT388 fused to human interleukin-3 (IL3). The new fusion protein does not bind monocytes nor induce secretion of cytokines. Remarkably, DT3881L3 binds and intoxicates leukemic progenitors from all types of myeloid leukemias. DT388IL3 is currently being manufactured under GMP at Wake Forest University. In this grant application, we request funding to complete the preclinical and preliminary clinical evaluation of DT388IL3. In Specific Aim 1, anti-leukemic efficacy will be tested in leukemic SCID mice. Specific Aim 2 will study safety in non-human primates bearing cross-reactive receptors. Results from these experiments will facilitate the submission of an INDA. Specific Aim 3 will determine the safe dose, dose-limiting toxicities, cytokine secretion, pharmacokinetics, and immune response and correlate toxicities with cytokine, DT388IL3 and anti-DT388IL3 blood levels. In a single-arm inter-patient dose escalation phase I clinical protocol, bolus infusions of DT388IL3 will be given to patients with relapsed or refractory AML. Specific Aim 4 will estimate the preliminary response rate and correlate it with drug and antibody levels, patients leukemic blast IL3 receptor content, and patient leukemic progenitor sensitivity in vitro. These studies will hopefully lead to the design of pivotal phase II and III clinical trials which will define the role of DT388IL3 in the management of AML.
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