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Target Overview
CD123, also known as interleukin-3 receptor alpha (IL-3Rα), is a transmembrane and heterodimeric receptor with biologic functions that plays an essential role in regulating the proliferation and differentiation of hematopoietic stem cells. CD123 is overexpressed in hematological malignancies, especially in the leukemic stem cell and at lower levels in the hematopoietic stem cell and more mature cells. CD123 overexpression has been widely described in AML, MDS, B-ALL and BPDCN.1 The prevalence of CD123 positive expression is high in AML (>90%)2,3,4 and has been reported in MDS related to progression and poor prognosis.5,6 CD123 expression has been associated with FLT3-ITD, NPM1 mutations and adverse cytogenetics.7
Compound Overview
AZD9829 is a fully humanized IgG antibody drug conjugate that binds with high affinity to IL-3Ra on the surface of cells that express CD123. Conjugated to the antibody is a topoisomerase I inhibitor (TOP1i) payload (AZ14170132) by a cleavable pegylated linker and with a drug antibody ratio of 8. After binding to the tumor cells, AZD9829 binds with greater affinity to CD123 positive cells limiting nonspecificity, gets internalized, and the released warhead causes DNA damage and apoptotic cell death.8
Mechanism of Action
References
1. Testa U, Pelosi E, Castelli G. Cancers (Basel). 2019;11(9):1358. 2. Bras AE, de Haas V, van Stigt A, et al. Cytometry B Clin Cytom. 2019;96(2):134–142. 3. Muñoz L, Nomdedéu JF, López O, et al. Haematologica. 2001;86(12):1261–1269. 4. Al-Mawali A, Gillis D, Lewis I. J Hematol Oncol. 2016;9(1):61. 5. Li LJ, Tao JL, Fu R, et al. Int J Hematol. 2014;100(1):60–69. 6. Zhang W, Shao Z, Fu R, et al. Clin Lab. 2015;61(10):1429–1434. 7. Ehninger A, Kramer M, Röllig C, et al. Blood Cancer J. 2014;4(6):e218. 8. Sordet O, Khan QA, Kohn KW, Pommier Y. Curr Med Chem Anticancer Agents. 2003;3(4):271-290.
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Abbreviations
ADC
antibody drug conjugate
AML
acute myeloid leukemia
B-ALL
B-cell acute lymphoblastic leukemia
BPDCN
blastic plasmacytoid dendritic cell neoplasm
CD123
cluster of differentiation
DAR
drug-to-antibody ratio
DNA
deoxyribonucleic acid
FLT3-ITD
FMS-like tyrosine kinase internal tandem duplication
IgG
immunoglobulin G
IL-3Rα
interleukin 3 receptor alpha
MDS
myelodysplastic syndrome
NPM1
nucleophosmin gene 1
R/R
relapsed/refractory
TOP1i
topoisomerase 1 inhibitor
Target Overview
CD123, also known as interleukin-3 receptor alpha (IL-3Rα), is a transmembrane and heterodimeric receptor with biologic functions that plays an essential role in regulating the proliferation and differentiation of hematopoietic stem cells. CD123 is overexpressed in hematological malignancies, especially in the leukemic stem cell and at lower levels in the hematopoietic stem cell and more mature cells. CD123 overexpression has been widely described in AML, MDS, B-ALL and BPDCN.1 The prevalence of CD123 positive expression is high in AML (>90%)2,3,4 and has been reported in MDS related to progression and poor prognosis.5,6 CD123 expression has been associated with FLT3-ITD, NPM1 mutations and adverse cytogenetics.7
Compound Overview
AZD9829 is a fully humanized IgG antibody drug conjugate that binds with high affinity to IL-3Ra on the surface of cells that express CD123. Conjugated to the antibody is a topoisomerase I inhibitor (TOP1i) payload (AZ14170132) by a cleavable pegylated linker and with a drug antibody ratio of 8. After binding to the tumor cells, AZD9829 binds with greater affinity to CD123 positive cells limiting nonspecificity, gets internalized, and the released warhead causes DNA damage and apoptotic cell death.8
Mechanism of Action
References
1. Testa U, Pelosi E, Castelli G. Cancers (Basel). 2019;11(9):1358. 2. Bras AE, de Haas V, van Stigt A, et al. Cytometry B Clin Cytom. 2019;96(2):134–142. 3. Muñoz L, Nomdedéu JF, López O, et al. Haematologica. 2001;86(12):1261–1269. 4. Al-Mawali A, Gillis D, Lewis I. J Hematol Oncol. 2016;9(1):61. 5. Li LJ, Tao JL, Fu R, et al. Int J Hematol. 2014;100(1):60–69. 6. Zhang W, Shao Z, Fu R, et al. Clin Lab. 2015;61(10):1429–1434. 7. Ehninger A, Kramer M, Röllig C, et al. Blood Cancer J. 2014;4(6):e218. 8. Sordet O, Khan QA, Kohn KW, Pommier Y. Curr Med Chem Anticancer Agents. 2003;3(4):271-290.
Clinical trial information
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Abbreviations
ADC
antibody drug conjugate
AML
acute myeloid leukemia
B-ALL
B-cell acute lymphoblastic leukemia
BPDCN
blastic plasmacytoid dendritic cell neoplasm
CD123
cluster of differentiation
DAR
drug-to-antibody ratio
DNA
deoxyribonucleic acid
FLT3-ITD
FMS-like tyrosine kinase internal tandem duplication
IgG
immunoglobulin G
IL-3Rα
interleukin 3 receptor alpha
MDS
myelodysplastic syndrome
NPM1
nucleophosmin gene 1
R/R
relapsed/refractory
TOP1i
topoisomerase 1 inhibitor