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Cardiovascular & Hematological Disorders-Drug Targets

Editor-in-Chief

ISSN (Print): 1871-529X
ISSN (Online): 2212-4063

Review Article

CD123: A Novel Biomarker for Diagnosis and Treatment of Leukemia

Author(s): Mingyue Shi, Ruijun J. Su, Kamal-Preet Parmar, Rahman Chaudhry, Kai Sun, Jianyu Rao and Mingyi Chen*

Volume 19, Issue 3, 2019

Page: [195 - 204] Pages: 10

DOI: 10.2174/1871529X19666190627100613

Price: $65

Abstract

Leukemia is a group of progressive hematologic malignancies derived from stem cells in bone marrow which causes a large number of cancer deaths. Even with treatment such as traditional chemotherapy, targeted therapy, and allogeneic stem cell transplantation (allo-HSCT), many patients suffer from relapse/refractory disease, and the overall survival is dismal. Leukemic stem cells (LSCs) are induced by gene mutations and undergo an aberrant and poorly regulated proliferation process which is involved in the evolution, relapse, and drug-resistance of leukemia. Emerging studies demonstrate that CD123, the interleukin 3 receptor alpha (IL-3Rα), is highly expressed in LSCs, while not normal hematopoietic stem cells (HSCs), and associates with treatment response, minimal residual disease (MRD) detection and prognosis. Furthermore, CD123 is an important marker for the identification and targeting of LSCs for refractory or relapsed leukemia. Anti-CD123 target-therapies in pre-clinical studies and clinical trials confirm the utility of anti-CD123 neutralizing antibody-drugs, CD3×CD123 bispecific antibodies, dual-affinity retargeting (DART), and anti-CD123 chimeric antigen receptor-modified T-cell (CAR-T) therapies in progress. This review summarizes the most recent progress on the study of CD123 biology and the development of novel CD123-targeted therapies.

Keywords: CD123, LSCs, refractory/relapse, leukemia, anti-CD123, hematologic malignant diseases.

Graphical Abstract
[1]
Surveillance, Epidemiology, And End Results (SEER) Program. www.seer.cancer.gov
[2]
Dombret, H.; Gardin, C. An update of current treatments for adult acute myeloid leukemia. Blood, 2016, 127(1), 53-61.
[3]
Sun, W.; Malvar, J.; Sposto, R.; Verma, A.; Wilkes, J.J.; Dennis, R.; Heym, K.; Laetsch, T.W.; Widener, M.; Rheingold, S.R.; Oesterheld, J.; Hijiya, N.; Sulis, M.L.; Huynh, V.; Place, A.E.; Bittencourt, H.; Hutchinson, R.; Messinger, Y.; Chang, B.; Matloub, Y.; Ziegler, D.S. Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: A therapeutic advances in childhood leukemia & lymphoma study. Leukemia, 2018, 32, 2316-2325.
[4]
Pollyea, D.A.; Gutman, J.A.; Gore, L.; Smith, C.A.; Jordan, C.T. Targeting acute myeloid leukemia stem cells: A review and principles for the development of clinical trials. Haematologica, 2014, 99(8), 1277-1284.
[5]
Zhou, H.; Xu, R. Leukemia stem cells: The root of chronic myeloid leukemia. Protein Cell, 2015, 6(6), 403-412.
[6]
Taussig, D.C.; Pearce, D.J.; Simpson, C.; Rohatiner, A.Z.; Lister, T.A.; Kelly, G.; Luongo, J.L.; Danet-Desnoyers, G.A.; Bonnet, D. Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood, 2005, 106(13), 4086-4092.
[7]
Liu, K.; Zhu, M.; Huang, Y.; Wei, S.; Xie, J.; Xiao, Y. CD123 and its potential clinical application in leukemias. Life Sci., 2015, 122, 59-64.
[8]
Testa, U.; Pelosi, E.; Frankel, A. CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies. Biomark. Res., 2014, 2(1), 4.
[9]
Fitz Gerald, D.J. Targeted diphtheria toxin to treat BPDCN. Blood, 2014, 124(3), 310-312.
[10]
Al-Mawali, A.; Gillis, D.; Lewis, I. Immunoprofiling of leukemic stem cells CD34+/CD38-/CD123+ delineate FLT3/ITD-positive clones. J. Hematol. Oncol., 2016, 9(1), 61.
[11]
Al-Mawali, A.; Pinto, A.D.; Al-Zadjali, S. CD34+CD38-CD123+ cells are present in virtually all acute myeloid leukaemia blasts: A promising single unique phenotype for minimal residual disease detection. Acta Haematol., 2017, 138(3), 175-181.
[12]
Ehninger, A.; Kramer, M.; Rollig, C.; Thiede, C.; Bornhauser, M.; von Bonin, M.; Wermke, M.; Feldmann, A.; Bachmann, M.; Ehninger, G.; Oelschlagel, U. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J., 2014, 4e218
[13]
Li, L.J.; Tao, J.L.; Fu, R.; Wang, H.Q.; Jiang, H.J.; Yue, L.Z.; Zhang, W.; Liu, H.; Shao, Z.H. Increased CD34+CD38-CD123+ cells in myelodysplastic syndrome displaying malignant features similar to those in AML. Internet J. Hematol., 2014, 100(1), 60-69.
[14]
Roug, A.S.; Larsen, H.O.; Nederby, L.; Just, T.; Brown, G.; Nyvold, C.G.; Ommen, H.B.; Hokland, P. hMICL and CD123 in combination with a CD45/CD34/CD117 backbone - a universal marker combination for the detection of minimal residual disease in acute myeloid leukaemia. Br. J. Haematol., 2014, 164(2), 212-222.
[15]
Djokic, M.; Bjorklund, E.; Blennow, E.; Mazur, J.; Soderhall, S.; Porwit, A. Overexpression of CD123 correlates with the hyperdiploid genotype in acute lymphoblastic leukemia. Haematologica, 2009, 94(7), 1016-1019.
[16]
Hassanein, N.M.; Alcancia, F.; Perkinson, K.R.; Buckley, P.J.; Lagoo, A.S. Distinct expression patterns of CD123 and CD34 on normal bone marrow B-cell precursors (“hematogones”) and B lymphoblastic leukemia blasts. Am. J. Clin. Pathol., 2009, 132(4), 573-580.
[17]
Zeidan, M.A.; Kamal, H.M.; El Shabrawy, D.A.; Esh, A.M.; Sattar, R.H. Significance of CD34/CD123 expression in detection of minimal residual disease in B-ACUTE lymphoblastic leukemia in children. Blood Cells Mol. Dis., 2016, 59, 113-118.
[18]
Du, W.; Li, J.; Liu, W.; He, Y.; Yao, J.; Liu, Y.; Lin, J.; Zheng, J. Interleukin-3 receptor alpha chain (CD123) is preferentially expressed in immature T-ALL and may not associate with outcomes of chemotherapy. Tumour Biol: J. Intern. Soc. Oncodevelop. Biol. Med, 2016, 37(3), 3817-3821.
[19]
Frolova, O.; Benito, J.; Brooks, C.; Wang, R.Y.; Korchin, B.; Rowinsky, E.K.; Cortes, J.; Kantarjian, H.; Andreeff, M.; Frankel, A.E.; Konopleva, M. SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia. Br. J. Haematol., 2014, 166(6), 862-874.
[20]
Ruella, M.; Klichinsky, M.; Kenderian, S.S.; Shestova, O.; Ziober, A.; Kraft, D.O.; Feldman, M.; Wasik, M.A.; June, C.H.; Gill, S. Overcoming the immunosuppressive tumor microenvironment of hodgkin lymphoma using chimeric antigen receptor T Cells. Cancer Discov., 2017, 7(10), 1154-1167.
[21]
Lin, J.; Chen, S.; Zhao, Z.; Cummings, O.W.; Fan, R. CD123 is a useful immunohistochemical marker to facilitate diagnosis of acute graft-versus-host disease in colon. Hum. Pathol., 2013, 44(10), 2075-2080.
[22]
Su, R.; Chen, M. CD123 is a useful marker for prediction of clinical outcome and risk stratification for prognosis in leukemia patients. Am. J. Clin. Pathol., 2015, 144, A139.
[23]
He, S.Z.; Busfield, S.; Ritchie, D.S.; Hertzberg, M.S.; Durrant, S.; Lewis, I.D.; Marlton, P.; McLachlan, A.J.; Kerridge, I.; Bradstock, K.F.; Kennedy, G.; Boyd, A.W.; Yeadon, T.M.; Lopez, A.F.; Ramshaw, H.S.; Iland, H.; Bamford, S.; Barnden, M.; DeWitte, M.; Basser, R.; Roberts, A.W. A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia. Leuk. Lymphoma, 2015, 56(5), 1406-1415.
[24]
Syed, K.; Pietsch, C.; Axel, A. Forslund, Ann.; Sasser, K.; Salvati, M. Preclinical evaluation of CSL362/JNJ-56022473 single agent in in vitro assays. Blood, 2015, 126, 4946.
[25]
Lee, E.M.; Yee, D.; Busfield, S.J.; McManus, J.F.; Cummings, N.; Vairo, G.; Wei, A.; Ramshaw, H.S.; Powell, J.A.; Lopez, A.F.; Lewis, I.D.; McCall, M.N.; Lock, R.B. Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice. Haematologica, 2015, 100(7), 914-926.
[26]
Han, L.; Jorgensen, J.L.; Brooks, C.; Shi, C.; Zhang, Q.; Nogueras Gonzalez, G.M.; Cavazos, A.; Pan, R.; Mu, H.; Wang, S.A.; Zhou, J.; Ai-Atrash, G.; Ciurea, S.O.; Rettig, M.; DiPersio, J.F.; Cortes, J.; Huang, X.; Kantarjian, H.M.; Andreeff, M.; Ravandi, F.; Konopleva, M. antileukemia efficacy and mechanisms of action of SL-101, a novel anti-CD123 antibody conjugate, in acute myeloid leukemia. Clin. Cancer Res., 2017, 23(13), 3385-3395.
[27]
Li, F.; Sutherland, M.K.; Yu, C.; Walter, R.B.; Westendorf, L.; Valliere-Douglass, J.; Pan, L.; Cronkite, A.; Sussman, D.; Klussman, K.; Ulrich, M.; Anderson, M.E.; Stone, I.J.; Zeng, W.; Jonas, M.; Lewis, T.S.; Goswami, M.; Wang, S.A.; Senter, P.D.; Law, C.L.; Feldman, E.J.; Benjamin, D.R. Characterization of SGN-CD123A, a potent cd123-directed antibody-drug conjugate for acute myeloid leukemia. Mol. Can. Therap., 2018, 17(2), 554-564.
[28]
Akiyama, T.; Takayanagi, S.; Maekawa, Y.; Miyawaki, K.; Jinnouchi, F.; Jiromaru, T.; Sugio, T.; Daitoku, S.; Kusumoto, H.; Shimabe, M.; Nishikawa, S.; Yamawaki, K.; Iijima, K.; Hiura, M.; Takahashi, T.; Kikushige, Y.; Iwasaki, H.; Akashi, K.; Tawara, T. First preclinical report of the efficacy and pd results of KHK2823, a non-fucosylated fully human monoclonal antibody against IL-3Rα. Blood, 2015, 126, 1349.
[29]
Kovtun, Y.; Jones, G.E.; Adams, S.; Harvey, L.; Audette, C.A.; Wilhelm, A.; Bai, C.; Adams, S.; Goldmacher, V.S.; Chari, C.; Chittenden, T.A. CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells. Blood Adv., 2018, 2(8), 848-858.
[30]
Chichili, G.R.; Huang, L.; Li, H.; Burke, S.; He, L.; Tang, Q.; Jin, L.; Gorlatov, S.; Ciccarone, V.; Chen, F.; Koenig, S.; Shannon, M.; Alderson, R.; Moore, P.A.; Johnson, S.; Bonvini, E.A. CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates. Sci. Transl. Med., 2015, 7(289)289ra282
[31]
Campagne, O.; Delmas, A.; Fouliard, S.; Chenel, M.; Chichili, G.R.; Li, H.; Alderson, R.; Scherrmann, J.M.; Mager, D.E. Integrated pharmacokinetic/pharmacodynamic model of a bispecific CD3xCD123 DART molecule in nonhuman primates: evaluation of activity and impact of immunogenicity. Clin. Cancer Res., 2018, 24(11), 2631-2641.
[32]
Seung, Y.; Pong, C.E.; Chen, H.; Phung, S.; Chan, E.E.; Endo, N.A.; Rashid, E.; Bonzon, C.; Leung, I.W.L.; Muchhal, U.S.; Moore, G.L.; Bernett, M.J.; Szymkowski, D.W.; Desjarlais, J.R. Immunotherapy with long-lived anti-CD123 × anti-CD3 bispecific antibodies stimulates potent t cell-mediated killing of human aml cell lines and of CD123+ Cells in monkeys: A potential therapy for acute myelogenous leukemia. Blood, 2014, 124, 2316.
[33]
Bonifant, C.L.; Szoor, A.; Torres, D.; Joseph, N.; Velasquez, M.P.; Iwahori, K.; Gaikwad, A.; Nguyen, P.; Arber, C.; Song, X.T.; Redell, M.; Gottschalk, S. CD123-engager T cells as a novel immuno-|therapeutic for acute myeloid leukemia. Mol. Ther. J. Am. Soc. Gene Ther., 2016, 24(9), 1615-1626.
[34]
Fan, M.; Li, M.; Gao, L.; Geng, S.; Wang, J.; Wang, Y.; Yan, Z.; Yu, L. Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia. J. Hematol. Oncol., 2017, 10(1), 151.
[35]
Luo, Y.; Chang, L.; Hu, Y.; Dong, L.; Wei, G.; Huang, H. First-in-man CD123-specific chimeric antigen receptor-modified t cells for the treatment of refractory acute myeloid leukemia. Blood, 2015, 126, 3778.
[36]
Monica, L.; Sugita, G.M.; Zong, H.; Ewing-Crystal, N.; Trujillo-Alonso, V.; Mencia-Trinchant, N.; Lam, L.; Cruz, N.M.; Galetto, R.; Gouble, A.; Hassane, D.C.; Smith, J.; Roboz, G.J. Allogeneic Tcrα/β deficient CAR T-cells targeting CD123 prolong overall survival of AML patient-derived xenografts. Blood, 2016, 128, 765.
[37]
Tasian, S.K.; Kenderian, S.S.; Shen, F.; Ruella, M.; Shestova, O.; Kozlowski, M.; Li, Y.; Schrank-Hacker, A.; Morrissette, J.J.D.; Carroll, M.; June, C.H.; Grupp, S.A.; Gill, S. Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. Blood, 2017, 129(17), 2395-2407.
[38]
Petrov, J.C.; Wada, M.; Pinz, K.G.; Yan, L.E.; Chen, K.H.; Shuai, X.; Liu, H.; Chen, X.; Leung, L.H.; Salman, H.; Hagag, N.; Liu, F.; Jiang, X.; Ma, Y. Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. Leukemia, 2018, 32(6), 1317-1326.
[39]
Zhang, W.; Stevens, B.M.; Budde, E.E.; Forman, S.J.; Jordan, C.T. Purev, E. Anti-CD123 CAR T-cell therapy for the treatment of myelodysplastic syndrome. Blood, 2017, 130, 1917.
[40]
Ruella, M.; Barrett, D.M.; Kenderian, S.S.; Shestova, O.; Hofmann, T.J.; Perazzelli, J.; Klichinsky, M.; Aikawa, V.; Nazimuddin, F.; Kozlowski, M.; Scholler, J.; Lacey, S.F.; Melenhorst, J.J.; Morrissette, J.J.; Christian, D.A.; Hunter, C.A.; Kalos, M.; Porter, D.L.; June, C.H.; Grupp, S.A.; Gill, S. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J. Clin. Invest., 2016, 126(10), 3814-3826.
[41]
Thokala, R.; Olivares, S.; Mi, T.; Maiti, S.; Deniger, D.; Huls, H.; Torikai, H.; Singh, H.; Champlin, R.E.; Laskowski, T.; McNamara, G.; Cooper, L.J. Redirecting specificity of t cells using the sleeping beauty system to express chimeric antigen receptors by mix-and-matching of VL and VH domains targeting CD123+ tumors. PLoS One, 2016, 11(8)e0159477
[42]
Nievergall, E.; Ramshaw, H.S.; Yong, A.S.; Biondo, M.; Busfield, S.J.; Vairo, G.; Lopez, A.F.; Hughes, T.P.; White, D.L.; Hiwase, D.K. Monoclonal antibody targeting of IL-3 receptor alpha with CSL362 effectively depletes CML progenitor and stem cells. Blood, 2014, 123(8), 1218-1228.
[43]
Sun, W.; Liu, H.; Kim, Y.; Karras, N.; Pawlowska, A.; Toomey, D.; Kyono, W.; Gaynon, P.; Rosenthal, J.; Stein, A. First pediatric experience of SL-401, a CD123-targeted therapy, in patients with blastic plasmacytoid dendritic cell neoplasm: Report of three cases. J. Hematol. Oncol., 2018, 11(1), 61.
[44]
Cai, T.; Galetto, R.; Gouble, A.; Smith, J.; Cavazos, A.; Konoplev, S.; Lane, A.A.; Guzman, M.L.; Kantarjian, H.M.; Pemmaraju, N.; Konopleva, M. Pre-clinical studies of allogeneic anti-CD123 CAR-T cells for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). Blood, 2016, 128, 4039.
[45]
Constine, L.S.; Yahalom, J.; Ng, A.K.; Hodgson, D.C.; Wirth, A.; Milgrom, S.A.; Mikhaeel, N.G.; Eich, H.T.; Illidge, T.; Ricardi, U.; Dieckmann, K.; Moskowitz, C.H.; Advani, R.; Mauch, P.M.; Specht, L.; Hoppe, R.T. The role of radiation therapy in patients with relapsed or refractory hodgkin lymphoma: Guidelines from the international lymphoma radiation oncology group. Intern. J. Rad. Oncol, Biol. Phy., 2018, 100(5), 1100-1118.
[46]
Xie, L.H.; Biondo, M.; Busfield, S.J.; Arruda, A.; Yang, X.; Vairo, G.; Minden, M.D. CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission. Blood Cancer J., 2017, 7(6) e567

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