Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody

Broughton, Sophie E.; Hercus, Timothy R.; Hardy, Matthew P.; McClure, Barbara J.; Nero, Tracy L.; Dottore, Mara; Huynh, Huy; Braley, Hal; Barry, Emma F.; Kan, Winnie L.; Dhagat, Urmi; Scotney, Pierre; Hartman, Dallas J.; Busfield, Samantha J.; Owczarek, Catherine M.; Nash, Andrew D.; Wilson, Nicholas J.; Parker, Michael W.; Lopez, Angel F.

doi:10.1016/j.celrep.2014.06.038

Cited by 48 publications

(68 citation statements)

References 29 publications

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“…A considerable amount is known about the structures of the ECDs of these receptors, beginning with the landmark crystal structure of the 2:1 complex of the archetypal dimeric GHR ECD with the GH [ 14 ]. Extracellular structures have subsequently been solved for several other members of the receptor family including the EPOR [ 16 ], PRLR [ 15 ], GM-CSFR [ 28 ], IL3Rα [ 29 ] IL-6R [ 30 , 31 ] and LIF-R [ 32 , 33 ]. Although all members of class I cytokine receptors have the characteristic two FNIII domain structure that is used to capture their ligand, there are distinct variations between similar groups of receptors within this class ( Figure 1 ).…”

Section: Class I Cytokine Receptorsmentioning

confidence: 99%

JAK2 activation by growth hormone and other cytokines

Waters

Brooks

2015

Biochemical Journal

113

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Growth hormone (GH) and structurally related cytokines regulate a great number of physiological and pathological processes. They do this by coupling their single transmembrane domain (TMD) receptors to cytoplasmic tyrosine kinases, either as homodimers or heterodimers. Recent studies have revealed that many of these receptors exist as constitutive dimers rather than being dimerized as a consequence of ligand binding, which has necessitated a new paradigm for describing their activation process. In the present study, we describe a model for activation of the tyrosine kinase Janus kinase 2 (JAK2) by the GH receptor homodimer based on biochemical data and molecular dynamics simulations. Binding of the bivalent ligand reorientates and rotates the receptor subunits, resulting in a transition from a form with parallel TMDs to one where the TMDs separate at the point of entry into the cytoplasm. This movement slides the pseudokinase inhibitory domain of one JAK kinase away from the kinase domain of the other JAK within the receptor dimer–JAK complex, allowing the two kinase domains to interact and trans-activate. This results in phosphorylation and activation of STATs and other signalling pathways linked to this receptor which then regulate postnatal growth, metabolism and stem cell activation. We believe that this model will apply to most if not all members of the class I cytokine receptor family, and will be useful in the design of small antagonists and agonists of therapeutic value.

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Section: Class I Cytokine Receptorsmentioning

confidence: 99%

JAK2 activation by growth hormone and other cytokines

Waters

Brooks

2015

Biochemical Journal

113

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“…CSL362 is a humanized therapeutic mAb that binds to CD123 and incorporates two mechanisms of action. It inhibits IL-3 binding to CD123, antagonizing IL-3 signaling in target cells (29,30). Second, the Fc region of CSL362 has been mutated to increase affinity for CD16 (FcγRIIIa), thereby enhancing antibody-To date, the major target of biologic therapeutics in systemic lupus erythematosus (SLE) has been the B cell, which produces pathogenic autoantibodies.…”

Section: Introductionmentioning

confidence: 99%

A cytotoxic anti-IL-3Rα antibody targets key cells and cytokines implicated in systemic lupus erythematosus

et al. 2016

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To date, the major target of biologic therapeutics in systemic lupus erythematosus (SLE) has been the B cell, which produces pathogenic autoantibodies. Recently, targeting type I IFN, which is elaborated by plasmacytoid dendritic cells (pDCs) in response to endosomal TLR7 and TLR9 stimulation by SLE immune complexes, has shown promising results. pDCs express high levels of the IL-3Rα chain (CD123), suggesting an alternative potential targeting strategy. We have developed an anti-CD123 monoclonal antibody, CSL362, and show here that it affects key cell types and cytokines that contribute to SLE. CSL362 potently depletes pDCs via antibody-dependent cell-mediated cytotoxicity, markedly reducing TLR7, TLR9, and SLE serum-induced IFN-α production and IFN-α-upregulated gene expression. The antibody also inhibits TLR7- and TLR9-induced plasmablast expansion by reducing IFN-α and IL-6 production. These effects are more pronounced than with IFN-α blockade alone, possibly because pDC depletion reduces production of other IFN subtypes, such as type III, as well as non-IFN proinflammatory cytokines, such as IL-6. In addition, CSL362 depletes basophils and inhibits IL-3 signaling. These effects were confirmed in cells derived from a heterogeneous population of SLE donors, various IFN-dependent autoimmune diseases, and healthy controls. We also demonstrate in vivo activity of CSL362 following its s.c. administration to cynomolgus monkeys. This spectrum of effects provides a preclinical rationale for the therapeutic evaluation of CSL362 in SLE.

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“…This drug is also shown to be able to eliminate cells expressing elevated levels of CD123, such as basophils, plasmacytoid dendritic cells, myeloid-derived suppressor cells, leukemic blasts, and leukemic stem cells. Of note, elimination of CD123 + MDS blasts, leukemic stem cells, and MDSCs thus offers a new therapeutic strategy for AML patients [49].…”

Section: Innate Immune System In Mdsmentioning

confidence: 99%

Novel combinations to improve hematopoiesis in myelodysplastic syndrome

et al. 2020

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Myelodysplastic syndrome (MDS) represents a heterogeneous group of clonal hematopoietic disorders, which is characterized by cytopenias in the peripheral blood and bone marrow dysplasia due to ineffective hematopoiesis. Patients with MDS have an increased risk of transformation to acute myeloid leukemia (AML). Although the molecular basis of MDS is heterogeneous, several studies demonstrated the significant contribution of the dysregulated immune system in accelerating MDS progression. The immunosuppressive tumor microenvironment is shown to induce tolerance of MDS blasts, which may result in a further accumulation of genetic aberrations and lead to the disease progression. Increasing evidence shows an expansion of myeloid-derived suppressor cells (MDSCs), a population of inflammation-associated immature cells, in patients with MDS. Interestingly, the increased MDSC populations are shown to be correlated with a risk of disease progression in MDS. In addition, MDS is highly prevalent in aged individuals with non-hematology co-morbidities who are fragile for chemotherapy. Increasing research effort is devoting to identify novel agents to specific targeting of the MDSC population for MDS treatment.

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Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody

Cited by 48 publications

References 29 publications

JAK2 activation by growth hormone and other cytokines

JAK2 activation by growth hormone and other cytokines

A cytotoxic anti-IL-3Rα antibody targets key cells and cytokines implicated in systemic lupus erythematosus

Novel combinations to improve hematopoiesis in myelodysplastic syndrome

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