Name:
Spesolimab mechanism of action in the treatment of generalized pustular psoriasis
Description:
Spesolimab mechanism of action in the treatment of generalized pustular psoriasis
Thumbnail URL:
https://cadmoremediastorage.blob.core.windows.net/de5eabf2-d97b-4755-9aa6-febc78dd10b5/videoscrubberimages/Scrubber_14.jpg
Duration:
T00H05M23S
Embed URL:
https://stream.cadmore.media/player/de5eabf2-d97b-4755-9aa6-febc78dd10b5
Content URL:
https://cadmoreoriginalmedia.blob.core.windows.net/de5eabf2-d97b-4755-9aa6-febc78dd10b5/BI303-23 Spesolimab MOA Animation_v6.mp4?sv=2019-02-02&sr=c&sig=yVkydMUiGbaRAS62RJdN6cIFo6k25PwuJXWQ1u3yLmg%3D&st=2024-11-21T09%3A03%3A12Z&se=2024-11-21T11%3A08%3A12Z&sp=r
Upload Date:
2024-11-05T00:00:00.0000000
Transcript:
Language: EN.
Segment:1 Introduction.
This video explains spesolimab's mechanism of action in the treatment of generalized pustular psoriasis. Dysfunction of the interleukin-36 axis has a key role in the pathogenesis of generalized pustular psoriasis, or GPP.
Segment:2 Normal IL-36 signalling.
To begin with, we will look at normal interleukin-36 signaling.
In the skin, interleukin-36 receptors are expressed in keratinocytes. A precipitating event triggers interleukin-36 expression in the keratinocytes. Interleukin-36 receptor activation occurs via binding of interleukin-36 agonists alpha, beta, and gamma to the interleukin-36 receptor. This causes recruitment of the interleukin-1 receptor accessory protein co-receptor, which leads to activation of intracellular adaptor proteins and downstream signaling pathways that stimulate increased gene expression of pro-inflammatory cytokines, and agents that promote chemotaxis and cell proliferation, resulting in a broad inflammatory response, keratinocyte proliferation, and neutrophil and T-cell chemotaxis.
Dendritic cells are activated by interleukin-36 and contribute to further inflammatory responses. Conversely, binding of the interleukin-36 receptor antagonist to the receptor restrains over-activation of interleukin-36 signaling by preventing recruitment of the accessory protein and blocks activation of downstream inflammatory responses.
Segment:3 Unrestrained IL-36 signalling in generalized pustular psoriasis.
Interleukin-36 signaling is unrestrained in people with GPP.
In people with GPP, functional interleukin-36 receptor antagonists may be overwhelmed by a huge excess of interleukin-36 agonists, resulting in incomplete receptor blockade. Up to around 70% of people with GPP may have bi-allelic loss-of-function mutations in the gene encoding the interleukin-36 receptor antagonist.
This results in faulty interleukin-36 receptor antagonist protein production. This faulty protein is unable to block the interleukin-36 receptor, and there is no inhibition of downstream inflammatory pathways. In either scenario, overactivation of the interleukin-36 axis occurs and results in further release of interleukin-36 agonists and products associated with inflammation.
This causes recruitment of immune cells, including T-cells, dendritic cells, and neutrophils. Neutrophils follow a chemokine gradient into the epidermis and move towards the stratum corneum. The highest expression of interleukin-36 and interleukin-17C occurs in the stratum granulosum, and induction of CXCL chemokines is maximal around the stratum granulosum / stratum corneum interface.
Neutrophils accumulate in the mid-epidermis to create individual pustules, and the microscopic spongiform pustules of Kogoj that are diagnostic of GPP. Much larger accumulations of neutrophils at the stratum granulosum / stratum corneum interface create "lakes of pus." This is driven by high expression of CXCL chemokines near the stratum corneum.
Segment:4 Spesolimab.
Spesolimab is a humanized monoclonal antibody that inhibits interleukin-36 signaling by binding specifically to the interleukin-36 receptor.
In people with GPP, intrinsic interleukin-36 receptor antagonism may be ineffective. Spesolimab blocks the interleukin-36 receptor and prevents downstream activation of pro-inflammatory pathways. In people with GPP flare, samples of skin and blood taken before and after intravenous spesolimab infusion show that spesolimab treatment is associated with rapid down-regulation of genes and biomarkers linked to key inflammatory processes, as shown in this gene expression heatmap.
The macroscopic effects of spesolimab on GPP flare are shown in these two patients before and after treatment with intravenous spesolimab. These images demonstrate the rapid effect of spesolimab in treating GPP. More recently, subcutaneous dosing of spesolimab was also shown to be effective for the prevention of GPP flares.
Segment:5 Conclusions.
SPEAKER: Our concluding points are presented on-screen. Thank you for watching.
