Abstract DDT02-04: SGN-CD33A: Preclinical and phase 1 interim clinical trial results of a CD33-directed PBD dimer antibody-drug conjugate for the treatment of acute myeloid leukemia (AML)
Authors: Dana A. Kennedy, Stephen C. Alley, Baiteng Zhao, Eric J. Feldman, Megan O'Meara, May Sutherland
Journal: Cancer Research (2015)

Abstract CD33 is expressed on the surface of myeloblasts in 85 to 90% of patients with AML and represents a promising target regardless of age, risk factors, or underlying mutational heterogeneity. SGN-CD33A is an antibody-drug conjugate (ADC) composed of an anti-CD33 antibody with engineered cysteines enabling uniform site-specific conjugation, conjugated to a pyrrolobenzodiazepine (PBD) dimer which binds DNA with high intrinsic affinity. The antibody and PBD dimer are conjugated via a cleavable dipeptide linker that is highly stable in circulation. Upon binding to the cell surface, SGN-CD33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker and diffuses inside the cell. PBD dimer crosslinks DNA, overwhelms DNA repair mechanisms, and triggers a cascade of events leading to cell death. SGN-CD33A is active as a single agent against a broad panel of primary AML samples and in multidrug-resistant preclinical models of AML (Sutherland 2013). Additionally, significant synergism in tumor cell killing was demonstrated in cytotoxicity assays when SGN-CD33A was combined with cytarabine, azacitidine, or decitabine (Sutherland 2014). Consistent with these observations, greater antitumor activity and reduced tumor growth were observed with these agents in combination with a single noncurative dose of SGN-CD33A in mouse xenograft models of multidrug resistant AML. The synergism with hypomethylating agents was associated with upregulation of CD33 expression on the cell surface of the AML cells as well as greater activation of the DNA damage sensor and apoptoticpathways. A first-in-human, phase 1, dose-escalation study of SGN-CD33A is ongoing to investigate the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD33A in patients with CD33-positive AML (NCT# 01902329). Patients must have either relapsed disease following initial complete remission (CR) of &amp;gt;3 months, or have declined conventional induction/consolidation. SGN-CD33A is administered outpatient IV every 3 weeks for up to 4 cycles (Part A), followed by optional maintenance treatment for patients achieving a CR/CRi (Part B). Investigator assessment of response is per IWG criteria (Cheson 2003). Another arm of the study will investigate the safety of SGN-CD33A in combination with either azacitidine or decitabine. Data have been reported on the first 56 patients who received SGN-CD33A as a single agent at doses ranging from 5−60 mcg/kg (presented by E. Stein at ASH 2014). Median age of patients was 75 years (range 27−86) and approximately 90% of patients had an ECOG performance score of 1. About half of the patients had received prior intensive therapy for AML, while the other half had declined intensive therapy. The most common adverse events considered related to SGN-CD33A included febrile neutropenia, fatigue, thrombocytopenia, anemia, and pyrexia. The 30-day mortality rate at the time of data presentation was 2% (1 patient whose death was not considered associated with SGN-CD33A). Preliminary pharmacokinetic data demonstrate rapid clearance of the ADC, suggesting target-mediated drug disposition. Among 52 patients evaluated for antitumor activity, 9 achieved CR or CR with incomplete hematologic recovery (CRi), 11 patients had clearance of blasts in their bone marrow (morphologic leukemia-free state, MLFS), and 29 patients had residual blasts in the bone marrow. The CR/CRi rate at 40 mcg/kg was 29% (5/17). The ongoing phase 1 study is evaluating SGN-CD33A as monotherapy and in combination with hypomethylating agents. Efforts are ongoing to refine a recommended dosing regimen for future study. Also enrolling is a phase 1b study of SGN-CD33A in combination with 7+3 chemotherapy in the frontline treatment of AML (NCT# NCT02326584). To date, preclinical data combined with emerging clinical safety and antitumor activity data form a foundation for the development of SGN-CD33A as a novel, targeted CD33-directed therapy for the treatment of AML and potentially other myeloid malignancies. Citation Format: Dana A. Kennedy, Stephen C. Alley, Baiteng Zhao, Eric J. Feldman, Megan O'Meara, May Sutherland. SGN-CD33A: Preclinical and phase 1 interim clinical trial results of a CD33-directed PBD dimer antibody-drug conjugate for the treatment of acute myeloid leukemia (AML). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT02-04. doi:10.1158/1538-7445.AM2015-DDT02-04