Project 4: Bi-specific antibody-based therapies for AML
Three-dimensional structure showing binding of the DNA methyltranferase 1 (DNMT1) inhibitor, RG-108, to the parent enzyme. Our data suggest that inhibition of DNMT1 leads to the production of regulatory T cells, which, in turn, reduce graft-versus-host disease.
The long-term goal of this project is to develop and translate into early phase clinical trials novel antibody-based reagents for the treatment of acute myelogenous leukemia (AML). Less than half of AML patients are cured with current treatment approaches, and relapse and refractory AML patients have a median overall survival of about 4 months. Allogeneic hematopoietic cell transplant (alloHCT) remains the only curative therapy for patients with relapsed and refractory AML. However, wider application of alloHCT has been limited by the morbidity associated with the procedure, which arises from graft-versus-host disease and from the toxicity of the pre-transplant conditioning regimen. In this proposal, we will utilize antibody-based immunotherapy approaches to treat AML relapse and allow for alloHCT without the need for chemotherapy and/or irradiation. In Aim 1, we will conduct a “first-in-human” Phase I clinical trial of AMV564, a CD33 x CD3 tetravalent bispecific antibody in patients with relapsed or refractory AML (ClinicalTrials.gov id: NCT03144245).
The bispecific AMV564 molecule binds to the CD3 molecule on T lymphocytes and the molecule CD33 on leukemia cells. This activates the patients’ own T lymphocytes to recognize and kill the leukemia cells. In Aim 2, we will determine if antibody-based drug conjugates can mitigate cytokine release syndrome (CRS) associated with T cell immunotherapeutics, kill AML blasts and provide conditioning for alloHSCT. We will utilize antibody-based reagents conjugated to toxins to simultaneously kill AML blasts (via CD45 or c-Kit) and condition the recipient for alloHCT by ablating host hematopoietic stem cells (via CD45 or c-Kit), and immune cells (T and NK cells via CD2 or CD7).