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bioRxiv · 10.1101/2020.10.09.334151

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models

Garg, R.·Allen, K. J.·Dawicki, W.·Geoghegan, E. M.·Ludwig, D. L.·Dadachova, E.
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Abstract

PurposeDespite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. 225Actinium-lintuzumab (225Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer. Experimental designHere we investigated the potential for 225Ac-lintuzumab-directed DNA damage to suppress MCL-1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML. ResultsWe demonstrated that 225Ac-lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax-resistant AML cell lines through both an induction of double-stranded DNA breaks (DSBs) and depletion of MCL-1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax-resistant in vivo AML models. ConclusionsThere results suggest that the combination of 225Ac-lintuzumab with venetoclax may be a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML.

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Garg, R., Allen, K. J., Dawicki, W., Geoghegan, E. M., Ludwig, D. L., Dadachova, E.. 2020-10-10. 225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. https://doi.org/10.1101/2020.10.09.334151

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