First-in Man, Phase 1 Study of CSL362 (Anti-IL3Rα / Anti-CD123 Monoclonal Antibody) in Patients with CD123+ Acute Myeloid Leukemia (AML) in CR at High Risk for Early Relapse

Smith, B. Douglas; Roboz, Gail J.; Walter, Roland B.; Altman, Jessica K.; Ferguson, Anna; Curcio, Tania J.; Orlowski, Kaysey F.; Garrett, Linda; Busfield, Samantha J.; Barnden, Megan; Sedgmen, Brad; Ghosh, Souravi; Hosback, Sarah; Davis, Roslyn; Dyson, Allison; Dasen, Sue; DeWitte, Mark; Bensen-Kennedy, Debra; Roberts, Andrew W.

doi:10.1182/blood.v124.21.120.120

Cited by 52 publications

(27 citation statements)

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“…A phase I trial in AML (clinical trial NCT01632852) using intravenously administered CSL362 in doses ranging from 0.3 to 12.0 mg/kg has recently been completed (43). In that study, there were no increased infections despite rapid (≤6 hours after dose) and complete pDC and basophil depletion at all doses for a fortnightly dosing frequency, which was sustained for ≥15 days for doses ≥3 mg/kg; however, a phase II trial will provide data regarding longer-term infection risk.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Strategies that use the immunological properties of antibodies to enhance antibody-dependent cell-mediated toxicity are also being pursued. Bispecific CD33 41 and CD123 42 antibodies linked to CD3 are being developed, as is a CD123 antibody linked to CD16, 43 meant to deliver cells expressing these targets into the vicinity of T cells or natural killer cells, respectively. Another novel approach involves targeting the CD47 antigen, preventing it from interacting with its cognate macrophage receptor SIRP1-a; preclinical studies have shown this disruption can lead to the activation of innate immunity and macrophage-mediated destruction of LSCs.…”

Section: Aberrant Immunophenotypesmentioning

confidence: 99%

Therapeutic targeting of acute myeloid leukemia stem cells

Pollyea

Jordan

2017

Blood

241

222

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For more than 50 years, investigators have considered a malignant stem cell as the potential origin of and a key therapeutic target for acute myeloid leukemia (AML) and other forms of cancer. The nature and existence of tumor-initiating cells for leukemia and other malignancies have long been the subject of intense and rigorous study; indeed, the promise of the potential to eradicate such cells is clear. However, until recently, deficiencies in our understanding of the nature of these cell populations, coupled with a limited ability to therapeutically exploit their weaknesses, have been limiting factors in realizing the goal of targeting leukemic stem cells (LSCs). Exciting new insights into the fundamental underpinnings of LSCs are now being made in an era in which drug development pipelines offer the potential to specifically target pathways of significance. Therefore, the focus in this new era, characterized by the confluence of understanding LSCs and the ability to target them, is shifting from "if it can be done" to "how it will be done." Moving from a theoretical stage to this hopeful era of possibilities, new challenges expectedly arise, and our focus now must shift to determining the best strategy by which to target LSCs, with their well-documented heterogeneity and readily evident intra- and interpatient variability. The purpose of this review is therefore both to summarize the key scientific findings pertinent to AML LSC targeting and to consider methods of clinical evaluation that will be most effective for identifying successful LSC-directed therapies.

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“…CSL362 is a humanized second-generation anti-CD123 antibody with favorable preclinical data [ 67 ] that was found to be safe and well tolerated as maintenance therapy in a phase I study of AML patients with CR + CRp and high risk of relapse (NCT01632852) [ 68 ]. A phase 2 study of CSL362 is planned.…”

Section: Immunotherapymentioning

confidence: 99%

Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia

Ramos

Karp

et al. 2015

JCM

106

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The limited sensitivity of the historical treatment response criteria for acute myeloid leukemia (AML) has resulted in a different paradigm for treatment compared with most other cancers presenting with widely disseminated disease. Initial cytotoxic induction chemotherapy is often able to reduce tumor burden to a level sufficient to meet the current criteria for “complete” remission. Nevertheless, most AML patients ultimately die from their disease, most commonly as clinically evident relapsed AML. Despite a variety of available salvage therapy options, prognosis in patients with relapsed or refractory AML is generally poor. In this review, we outline the commonly utilized salvage cytotoxic therapy interventions and then highlight novel investigational efforts currently in clinical trials using both pathway-targeted agents and immunotherapy based approaches. We conclude that there is no current standard of care for adult relapsed or refractory AML other than offering referral to an appropriate clinical trial.

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First-in Man, Phase 1 Study of CSL362 (Anti-IL3Rα / Anti-CD123 Monoclonal Antibody) in Patients with CD123+ Acute Myeloid Leukemia (AML) in CR at High Risk for Early Relapse

Cited by 52 publications

References 0 publications

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

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

Therapeutic targeting of acute myeloid leukemia stem cells

Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia

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