Dose selection of siltuximab for multicentric Castleman’s disease

Mayer, Christina; Xie, Lanyi; Bandekar, Rajesh; Qi, Ming; Velde, Helgi van de; Reddy, Manjula; Qin, Xiang; Davis, Hugh M.; Puchalski, Thomas A.

doi:10.1007/s00280-015-2720-0

Cited by 10 publications

(24 citation statements)

References 37 publications

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“…In practice, the assay for measuring total target is often not sensitive enough to detect the baseline target concentration before the drug is given, as was the case for siltuximab . Although the steady‐state plateau

(T_{tot, ss})

and the time scale for reaching it

(k_{eDT})

can still be identified, the baseline target level ( T 0 ) is no longer identifiable and this leads to unidentifiability of

K_{d}

as well.…”

Section: Methods and Resultsmentioning

confidence: 99%

“…Even though the AFIR equation demonstrates that the free target concentration will continue to decline with increasing dose, there may be a threshold (e.g., 5%) such that further reduction in AFIR no longer leads to improved clinical efficacy. Understanding this process can be aided with collection of a downstream pharmacodynamic biomarker (e.g., C‐reactive protein and neutrophil levels for anti‐IL‐6 therapy). Finally, AFIR should not be applied to agonists like TGN1412 16 or blinatumomab, where only small amounts of target binding (

AFIR > 90 %

) are necessary.…”

Section: Discussionmentioning

confidence: 99%

“…Antibodies with soluble targets (e.g., omalizumab/Immunoglobulin E, bevacizumab/vascular endothelial growth factor, siltuximab/interleukin‐6) often demonstrate significant target accumulation after single ( Figure a,b ) or repeated dosing ( Figure c ) because the mAb‐target complex often has a much longer half‐life than the free target molecules . Although this accumulation plateaus at large doses, this plateau does not necessarily imply a plateau in efficacy; and increasing the dose after the plateau has been associated with further reduction of the free target concentration, greater inhibition of downstream biomarkers, and improved efficacy …”

Section: Model Parameters For Omalizumab (One‐compartment Subcutaneomentioning

confidence: 99%

“…Antibodies with soluble targets (e.g., omalizumab/Immunoglobulin E, bevacizumab/vascular endothelial growth factor, siltuximab/ interleukin-6) often demonstrate significant target accumulation after single (Figure 1a,b) or repeated dosing ( Figure 1c) because the mAb-target complex often has a much longer half-life than the free target molecules. [3][4][5] Although this accumulation plateaus at large doses, this plateau does not necessarily imply a plateau in efficacy; and increasing the dose after the plateau has been associated with further reduction of the free target concentration, 6 greater inhibition of downstream biomarkers, 7,8 and improved efficacy. 9,10 To understand why the plateau in total target concentration does not imply a plateau in efficacy, and to understand how changes in the dose regimen or drug properties may impact target engagement, it is useful to characterize the free and bound concentrations for the drug and target using the model in Figure 2, which describes both TMDD and the accumulation of total target during therapy.…”

Section: What Question Did This Study Address?mentioning

confidence: 99%

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AFIR: A Dimensionless Potency Metric for Characterizing the Activity of Monoclonal Antibodies

Stein

Ramakrishna

2017

CPT Pharmacom & Syst Pharma

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For monoclonal antibody (mAb) drugs, soluble targets may accumulate several thousand fold after binding to the drug. Time course data of mAb and total target is often collected and, although free target is more closely related to clinical effect, it is difficult to measure. Therefore, mathematical models of this data are used to predict target engagement. In this article, a “potency factor” is introduced as an approximation for the model‐predicted target inhibition. This potency factor is defined to be the time‐Averaged Free target concentration to Initial target concentration Ratio (AFIR), and it depends on three key quantities: the average drug concentration at steady state; the binding affinity; and the degree of target accumulation. AFIR provides the intuition for how changes in dosing regimen and binding affinity affect target capture and AFIR can be used to predict the druggability of new targets and the expected benefits of more potent, second‐generation mAbs.

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(T_{tot, ss})

and the time scale for reaching it

(k_{eDT})

can still be identified, the baseline target level ( T 0 ) is no longer identifiable and this leads to unidentifiability of

K_{d}

as well.…”

Section: Methods and Resultsmentioning

confidence: 99%

AFIR > 90 %

) are necessary.…”

Section: Discussionmentioning

confidence: 99%

Section: Model Parameters For Omalizumab (One‐compartment Subcutaneomentioning

confidence: 99%

Section: What Question Did This Study Address?mentioning

confidence: 99%

See 2 more Smart Citations

AFIR: A Dimensionless Potency Metric for Characterizing the Activity of Monoclonal Antibodies

Stein

Ramakrishna

2017

CPT Pharmacom & Syst Pharma

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“…Another anti-IL-6 mAb, siltuximab, binds highly to IL-6, neutralizing its bioactivity [81]. It has been studied in various malignancies, including myelodysplastic syndrome, prostate cancer, and renal cell carcinoma (RCC) [82–85], and is under study in multiple myeloma (NCT01484275).…”

Section: Blocking Stat3 Activation: Targeting Upstream Receptorsmentioning

confidence: 99%

The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations

2016

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SUMMARY Proteins of the signal transducer and activator of transcription (STAT) family mediate cellular responses to cytokines and growth factors. Aberrant regulation of the STAT3 oncogene contributes to tumor formation and progression in many cancers, including head and neck squamous cell carcinoma (HNSCC), where hyperactivation of STAT3 is implicated in both treatment resistance and immune escape. There are no oncogenic gain-of-function mutations in HNSCC. Rather, aberrant STAT3 signaling is primarily driven by upstream growth factor receptors, such as Janus kinase (JAK) and epidermal growth factor receptor (EGFR). Moreover, genomic silencing of select protein tyrosine phosphatase receptors (PTPRs), tumor suppressors that dephosphorylate STAT3, may lead to prolonged phosphorylation and activation of STAT3. This review will summarize current knowledge of the STAT3 pathway and its contribution to HNSCC growth, survival, and resistance to standard therapies, and discuss STAT3-targeting agents in various phases of clinical development.

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A New Approach to the Management of COVID-19. Antagonists of IL-6: Siltuximab

et al. 2022

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Since the beginning of the pandemic, numerous national and international clinical trials have been conducted with a large number of drugs. Many of them are intended for the treatment of other pathologies; however, despite the great effort made, no specific drug is available for the treatment of the symptoms of respiratory disease caused by SARS-CoV-2 infection. The aim of this article is to provide data to justify the use of drugs to tackle the effects produced by IL-6 as the main inflammatory mediator in patients with COVID-19 with severe respiratory complications, considering all clinical evidence linking the poor prognosis of these patients with increased IL-6 levels in the context of cytokine release syndrome. Furthermore, data are provided to justify the proposal of a rational dosing of siltuximab, a monoclonal antibody specifically targeting IL-6, based on RCP levels, considering the limited results published so far on the use of this drug in COVID-19. A literature search was conducted on the clinical trials of siltuximab published to date as well as on the different IL-6 signalling pathways and the effects of its overexpression. Knowledge of the mechanisms of action on these pathways may provide important information for the design of drugs useful in the treatment of these patients. This article describes the characteristics, properties, mechanism of action, therapeutic uses and clinical studies conducted with siltuximab so far. The results confirm that administration of siltuximab downregulates IL-6 levels, thereby reducing the inflammatory process in COVID-19 patients with severe respiratory disease, suggesting that it can be successfully used to prevent cytokine release syndrome and death from this cause.

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Dose selection of siltuximab for multicentric Castleman’s disease

Cited by 10 publications

References 37 publications

AFIR: A Dimensionless Potency Metric for Characterizing the Activity of Monoclonal Antibodies

AFIR: A Dimensionless Potency Metric for Characterizing the Activity of Monoclonal Antibodies

The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations

A New Approach to the Management of COVID-19. Antagonists of IL-6: Siltuximab

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