TY - JOUR
T1 - Characterization of SGN-CD123A, APotent CD123-directed antibody-drug conjugate for acute myeloid leukemia
AU - Li, Fu
AU - Sutherland, May Kung
AU - Yu, Changpu
AU - Walter, Roland B.
AU - Westendorf, Lori
AU - Valliere-Douglass, John
AU - Pan, Lucy
AU - Cronkite, Ashley
AU - Sussman, Django
AU - Klussman, Kerry
AU - Ulrich, Michelle
AU - Anderson, Martha E.
AU - Stone, Ivan J.
AU - Zeng, Weiping
AU - Jonas, Mechthild
AU - Lewis, Timothy S.
AU - Goswami, Maitrayee
AU - Wang, Sa A.
AU - Senter, Peter D.
AU - Law, Che Leung
AU - Feldman, Eric J.
AU - Benjamin, Dennis R.
N1 - Publisher Copyright:
© 2017 AACR.
PY - 2018/2
Y1 - 2018/2
N2 - Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Ra, 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 stemcells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGNCD123A, 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 SGNCD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248).
AB - Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Ra, 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 stemcells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGNCD123A, 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 SGNCD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248).
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U2 - 10.1158/1535-7163.MCT-17-0742
DO - 10.1158/1535-7163.MCT-17-0742
M3 - Article
C2 - 29142066
AN - SCOPUS:85041483608
SN - 1535-7163
VL - 17
SP - 554
EP - 564
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 2
ER -