Abstract
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. 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. 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. 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.
Highlights
The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years, and most patients have poor long-term survival
We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent antibody–drug conjugate (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
Summary
CLL-1 has similar copy number and prevalence in AML as CD33 First, we wanted to validate the expression of CLL-1 in patients with AML as a potential ADC target by comparing it with the well-validated and prevalent target, CD33. Because CLL-1 expression is limited to the myeloid population of normal human peripheral blood leukocytes, we wanted to compare its expression level with bone marrow samples from patients with AML. To further understand the therapeutic potential of anti–CLL1-ds-PBD, we assessed the antitumor activity in various xenograft tumor models established in immunocompromised C.B-17 Fox Chase SCID mice from the same three human AML cell lines used above. These models expressed CLL-1 at levels within the range observed in patients with AML as determined by FACS (Fig. 4A) and harbor cytogenetic features of patients with AML that typically have poor prognosis. No decreases in neutrophils, lymphocytes, or platelets were observed in animals administered anti–gD-ds-PBD ADC
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