An Anti-CLL-1 Antibody-Drug Conjugate for the Treatment of Acute Myeloid Leukemia
| Autor: | Wei-Ching Liang, Cecilia Chiu, Steven R. Leong, Angela Hendricks, Vanessa Clark, Andrew Polson, Yan Wu, Rajesh Vij, Jack Sadowsky, Wayne Chu, Thomas H. Pillow, John A. Flygare, Genee Y. Lee, Geoffrey Del Rosario, Melissa Schutten, Shang-Fan Yu, Kirsten Achilles Poon, Cecile Chalouni, Bing Zheng |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Antibody-drug conjugate Myeloid Immunoconjugates CD33 Sialic Acid Binding Ig-like Lectin 3 03 medical and health sciences Mice 0302 clinical medicine hemic and lymphatic diseases medicine Animals Humans Lectins C-Type business.industry Myeloid leukemia medicine.disease Flow Cytometry Xenograft Model Antitumor Assays Antibodies Anti-Idiotypic body regions Gene Expression Regulation Neoplastic Leukemia Haematopoiesis Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Receptors Mitogen Cytarabine Cancer research Stem cell business medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 25(4) |
| ISSN: | 1557-3265 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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