» Articles » PMID: 24598927

Crystallization and Preliminary X-ray Diffraction Analysis of the Interleukin-3 Alpha Receptor Bound to the Fab Fragment of Antibody CSL362

Abstract

Interleukin-3 (IL-3) is a member of the beta common family of cytokines that regulate multiple functions of myeloid cells. The IL-3 receptor-specific alpha subunit (IL3Rα) is overexpressed on stem cells/progenitor cells of patients with acute myeloid leukaemia, where elevated receptor expression correlates clinically with a reduced patient survival rate. The monoclonal antibody (MAb) CSL362 is a humanized MAb derived from the murine MAb 7G3, originally identified for its ability to specifically recognize the human IL-3 receptor and for blocking the signalling of IL-3 in myeloid and endothelial cells. In order to elucidate the molecular mechanism of CSL362 antagonism, a preliminary structure of human IL3Rα in complex with the MAb CSL362 has been determined.

Citing Articles

Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.

Kan W, Dhagat U, Kaufmann K, Hercus T, Nero T, Zeng A Cancer Discov. 2023; 13(8):1922-1947.

PMID: 37191437 PMC: 10401075. DOI: 10.1158/2159-8290.CD-22-1396.


SIRPα-αCD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells.

Tahk S, Vick B, Hiller B, Schmitt S, Marcinek A, Perini E J Hematol Oncol. 2021; 14(1):155.

PMID: 34579739 PMC: 8477557. DOI: 10.1186/s13045-021-01163-6.


A dual role for the N-terminal domain of the IL-3 receptor in cell signalling.

Broughton S, Hercus T, Nero T, Kan W, Barry E, Dottore M Nat Commun. 2018; 9(1):386.

PMID: 29374162 PMC: 5785977. DOI: 10.1038/s41467-017-02633-7.


Novel CD123-aptamer-originated targeted drug trains for selectively delivering cytotoxic agent to tumor cells in acute myeloid leukemia theranostics.

Wu H, Wang M, Dai B, Zhang Y, Yang Y, Li Q Drug Deliv. 2017; 24(1):1216-1229.

PMID: 28845698 PMC: 8241133. DOI: 10.1080/10717544.2017.1367976.

References
1.
Jordan C, Upchurch D, Szilvassy S, Guzman M, Howard D, PETTIGREW A . The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000; 14(10):1777-84. DOI: 10.1038/sj.leu.2401903. View

2.
Matthews B . Some crystal forms of bovine chymotrypsinogen B and chymotrypsinogen A. J Mol Biol. 1968; 33(2):499-501. DOI: 10.1016/0022-2836(68)90206-4. View

3.
Stomski F, Sun Q, Bagley C, Woodcock J, Goodall G, Andrews R . Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding. Mol Cell Biol. 1996; 16(6):3035-46. PMC: 231298. DOI: 10.1128/MCB.16.6.3035. View

4.
Guthridge M, Stomski F, Thomas D, Woodcock J, Bagley C, Berndt M . Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors. Stem Cells. 1998; 16(5):301-13. DOI: 10.1002/stem.160301. View

5.
Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C . Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 1999; 96(22):12804-9. PMC: 23105. DOI: 10.1073/pnas.96.22.12804. View