Characterization of SGN-CD123A, A Potent CD123-Directed Antibody-Drug Conjugate for Acute Myeloid Leukemia
Fu Li1, May Kung Sutherland2, Changpu Yu2
1Translational Research, Seattle Genetics, Inc. Bothell, Washington. fli@seagen.com.
Abstract:
Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Rα, or CD123) is expressed on the majority of AML blasts, and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate using the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A-mediated potent cytotoxicity of 11/12 CD123+ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248). Mol Cancer Ther; 17(2); 554-64. ©2017 AACR.
Insights
A new antibody-drug conjugate, SGN-CD123A, shows potent anti-leukemic activity against acute myelogenous leukemia (AML) by targeting CD123. Preclinical studies demonstrate its efficacy in various AML models, supporting clinical trials.
Area of Science:
- Oncology
- Hematology
- Pharmacology
Background:
- Acute myelogenous leukemia (AML) presents limited treatment options for patients resistant to chemotherapy.
- Interleukin-3 receptor alpha (IL3Rα, or CD123) is a promising therapeutic target in AML due to its overexpression on leukemia cells.
- Novel antibody-based therapies are needed to address chemotherapy resistance in AML.
Purpose of the Study:
- To generate and characterize SGN-CD123A, a novel antibody-drug conjugate targeting CD123 for AML treatment.
- To evaluate the preclinical efficacy and mechanism of action of SGN-CD123A in vitro and in vivo.
- To assess the potential of SGN-CD123A in combination with other therapies for AML.
Main Methods:
- Development of SGN-CD123A, an antibody-drug conjugate utilizing a pyrrolobenzodiazepine dimer (PBD) payload and a humanized CD123 antibody with site-specific conjugation.
- In vitro assessment of SGN-CD123A's cytotoxicity against CD123+ AML cell lines and primary patient samples.
- In vivo evaluation of SGN-CD123A in disseminated, subcutaneous, and multidrug resistance xenograft models, including patient-derived xenografts.
- Combination studies of SGN-CD123A with the FLT3 inhibitor quizartinib in relevant AML models.
Main Results:
- SGN-CD123A demonstrated potent cytotoxicity in vitro against a majority of AML cell lines and primary samples, including those with poor prognostic markers.
- In vivo studies showed SGN-CD123A achieved AML eradication, remission, and significant growth delay in various xenograft models.
- SGN-CD123A induced durable complete remission in a patient-derived xenograft AML model.
- Combination therapy with quizartinib enhanced anti-leukemic activity in FLT3-mutated AML models.
Conclusions:
- SGN-CD123A is a potent antileukemic agent with a favorable preclinical profile against acute myelogenous leukemia.
- The data support the ongoing clinical evaluation of SGN-CD123A in AML patients.
- Targeting CD123 with antibody-drug conjugates represents a promising therapeutic strategy for AML, particularly in resistant cases.
