Bing Zheng 1 , Shang-Fan Yu 2 , Geoffrey Del Rosario 2 , Steven R Leong 2 , Genee Y Lee 2 , Rajesh Vij 2 , Cecilia Chiu 2 , Wei-Ching Liang 2 , Yan Wu 2 , Cecile Chalouni 2 , Jack Sadowsky 2 , Vanessa Clark 2 , Angela Hendricks 2 , Kirsten Achilles Poon 2 , Wayne Chu 2 , Thomas Pillow 2 , Melissa M Schutten 2 , John Flygare 2 , Andrew G Polson 1 Show Affiliations »
Abstract
PURPOSE: The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years. Cytarabine- and anthracycline-based chemotherapy induction regimens (7 + 3) remain the standard of care, and most patients have poor long-term survival. The reapproval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has demonstrated ADCs as a clinically validated option to enhance the effectiveness of induction therapy. We are interested in developing a next-generation ADC for AML to improve upon the initial success of Mylotarg. EXPERIMENTAL DESIGN: The expression pattern of CLL-1 and its hematopoietic potential were investigated. A novel anti-CLL-1-ADC, with a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker, was developed. The efficacy and safety profiles of this ADC were evaluated in mouse xenograft models and in cynomolgus monkeys. RESULTS: We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent ADC target for AML, but lacks expression on hematopoietic stem cells that hampers current CD33-targeted ADCs. Our anti-CLL-1-ADC is highly effective at depleting tumor cells in AML xenograft models and lacks target independent toxicities at doses that depleted target monocytes and neutrophils in cynomolgus monkeys. CONCLUSIONS: Collectively, our data suggest that an anti-CLL-1-ADC has the potential to become an effective and safer treatment for AML in humans, by reducing and allowing for faster recovery from initial cytopenias than the current generation of ADCs for AML. ©2018 American Association for Cancer Research.
PURPOSE: The treatment of acute myeloid leukemia (AML ) has not significantly changed in 40 years. Cytarabine - and anthracycline -based chemotherapy induction regimens (7 + 3) remain the standard of care, and most patients have poor long-term survival. The reapproval of Mylotarg, an anti-CD33 -calicheamicin antibody-drug conjugate (ADC), has demonstrated ADCs as a clinically validated option to enhance the effectiveness of induction therapy. We are interested in developing a next-generation ADC for AML to improve upon the initial success of Mylotarg. EXPERIMENTAL DESIGN: The expression pattern of CLL-1 and its hematopoietic potential were investigated. A novel anti-CLL-1 -ADC, with a highly potent pyrrolobenzodiazepine (PBD ) dimer conjugated through a self-immolative disulfide linker, was developed. The efficacy and safety profiles of this ADC were evaluated in mouse xenograft models and in cynomolgus monkeys . RESULTS: We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent ADC target for AML , but lacks expression on hematopoietic stem cells that hampers current CD33 -targeted ADCs. Our anti-CLL-1 -ADC is highly effective at depleting tumor cells in AML xenograft models and lacks target independent toxicities at doses that depleted target monocytes and neutrophils in cynomolgus monkeys . CONCLUSIONS: Collectively, our data suggest that an anti-CLL-1 -ADC has the potential to become an effective and safer treatment for AML in humans , by reducing and allowing for faster recovery from initial cytopenias than the current generation of ADCs for AML . ©2018 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
Species
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Year: 2018
PMID： 29959143 DOI： 10.1158/1078-0432.CCR-18-0333
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531