Abstract
Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Rα, or CD123) is expressed on the majority of AML blasts, and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate using the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A-mediated potent cytotoxicity of 11/12 CD123+ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248). Mol Cancer Ther; 17(2); 554-64. ©2017 AACR.
Highlights
Acute myelogenous leukemia (AML) is the most common form of adult leukemia and patients with AML need new therapies
Because it is possible that FLT3 mutated AML patients will receive both a FLT3 inhibitor and SGN-CD123A during clinical studies, we evaluated whether the combination of quizartinib, a FLT3-ITD
Induction chemotherapy can be effective in some patients, between 10% and 40% of newly diagnosed AML patients are refractory or resistant to the regimen
Summary
Acute myelogenous leukemia (AML) is the most common form of adult leukemia and patients with AML need new therapies. The older patients who are unable to receive intensive chemotherapy have an extremely poor prognosis, with a median overall survival between 5 and 10 months [1, 2]. For younger and fit patients, the intensive treatment options include multiagent chemotherapy with or without allogeneic hematopoietic stem cell transplant. Most AML patients will experience disease recurrence. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Law: Harpoon Therapeutics, South San Francisco, CA
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