Soluble interleukin-6 receptor in the COVID-19 cytokine storm syndrome

Chen, Luke Y C; Biggs, Catherine M.; Jamal, Shahin; Stukas, Sophie; Wellington, Cheryl L.; Sekhon, Mypinder S.

doi:10.1016/j.xcrm.2021.100269

Cited by 51 publications

(54 citation statements)

References 15 publications

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“…Cytokine profiling with measurement of serum levels of the proinflammatory cytokines interleukin-5 (IL-5), IL-6, interleukin-10 (IL-10), interleukin-17A (IL-17A), interferon-gamma (IFN-g), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor alpha (TNF-a) in patients who developed CRS after CD3-engaging bispecific antibody APVO436 indicates that the predominant cytokine in this inflammatory cytokine response is IL-6 [58]. The administration of Tocilizumab (antibody against IL-6:IL-6R) or Siltuximab (antibody against IL-6) at standard doses with or without dexamethasone rendered APVO436-associated severe CRS manageable and rapidly transient consistent with our current understanding of the IL-6 receptor signaling [59] and the standard management of this class-specific complication [27][28][29].…”

Section: Discussionmentioning

confidence: 57%

“…Older patients with newly diagnosed AML respond poorly to standard induction chemotherapy and have a poor survival. For newly diagnosed older AML patients, new treatment regimens have been developed in recent years, such the combination of the BCL-2 homology 3 (BH3)-mimetic compound; Venetoclax with HMA (e.g., azacitidine/AZA and decitabine/DAC); or the combination of the Hedgehog pathway inhibitor Glasdegib with LDARAC, both of which showed significant clinical activity with reduction in the risk of death in randomized phase II clinical trials [3,4,11,59]. Older patients with relapsed AML have a dismal prognosis and are in urgent need for new salvage treatment strategies for their chemo-resistant leukemia.…”

Section: Discussionmentioning

confidence: 99%

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A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Uckun

Lin

Mims

et al. 2021

Cancers

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APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1–8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Uckun

Lin

Mims

et al. 2021

Cancers

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“…Therefore, we consider that validating the model in a different cohort of patients in the future would be essential to give consistency to the results. (iii) The most relevant buffering system in the COVID-cytokine storm is the IL-6: sIL-6R:sgp130 system in trans signaling, which has been described in recent publications [ 37 , 38 ]. Thus, an inherent limitation of these multi-PLEX cytokine studies is that they typically only measure the cytokine itself, whereas there are other aspects of these cytokine signaling pathways that are omitted.…”

Section: Discussionmentioning

confidence: 99%

HGF, IL-1α, and IL-27 Are Robust Biomarkers in Early Severity Stratification of COVID-19 Patients

Tamayo-Velasco

Martínez-Paz

Peñarrubia-Ponce

et al. 2021

JCM

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Pneumonia is the leading cause of hospital admission and mortality in coronavirus disease 2019 (COVID-19). We aimed to identify the cytokines responsible for lung damage and mortality. We prospectively recruited 108 COVID-19 patients between March and April 2020 and divided them into four groups according to the severity of respiratory symptoms. Twenty-eight healthy volunteers were used for normalization of the results. Multiple cytokines showed statistically significant differences between mild and critical patients. High HGF levels were associated with the critical group (OR = 3.51; p < 0.001; 95%CI = 1.95–6.33). Moreover, high IL-1α (OR = 1.36; p = 0.01; 95%CI = 1.07–1.73) and low IL-27 (OR = 0.58; p < 0.005; 95%CI = 0.39–0.85) greatly increased the risk of ending up in the severe group. This model was especially sensitive in order to predict critical status (AUC = 0.794; specificity = 69.74%; sensitivity = 81.25%). Furthermore, high levels of HGF and IL-1α showed significant results in the survival analysis (p = 0.033 and p = 0.011, respectively). HGF, IL-1α, and IL 27 at hospital admission were strongly associated with severe/critical COVID-19 patients and therefore are excellent predictors of bad prognosis. HGF and IL-1α were also mortality biomarkers.

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“…Although IL-6 concentrations have been historically used as a surrogate for clinical response in chronic inflammatory conditions, recent evidence suggests that sIL-6R may be a more informative marker of immune dysregulation and a better predictor of tocilizumab response [40, 48]. Correspondingly, sIL-6R may also be a better surrogate for clinical response with tocilizumab in COVID-19.…”

Section: Introduction/backgroundmentioning

confidence: 99%

“…Correspondingly, sIL-6R may also be a better surrogate for clinical response with tocilizumab in COVID-19. The proposed rationale for evaluating sIL-6R response is that trans-signaling via sIL-6R may provide a more complete picture of clinically relevant IL-6 activity in vivo [48]. Nishimoto conducted a tocilizumab PK/PD study in patients with RA and Castleman Disease and found that “as long as free tocilizumab was detectable, sIL-6R was saturated and IL-6 signaling was completely inhibited” [35].…”

Section: Introduction/backgroundmentioning

confidence: 99%

Pharmacokinetic /Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19

Leung

Jorgensen

Crass³

et al. 2021

Preprint

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Tocilizumab is one of few treatments that have been shown to improve mortality in patients with COVID-19, but increased demand has led to relative global shortages. Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters which likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, though weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/PD insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.

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Soluble interleukin-6 receptor in the COVID-19 cytokine storm syndrome

Cited by 51 publications

References 15 publications

A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

HGF, IL-1α, and IL-27 Are Robust Biomarkers in Early Severity Stratification of COVID-19 Patients

Pharmacokinetic /Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19

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