How ZEPOSIA works

How ZEPOSIA works

Sphingosine-1-phosphate and ZEPOSIA (ozanimod) mechanism of action

What is Sphingosine-1-phosphate?

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator derived from the metabolism of membrane sphingolipids that plays an important role in several cellular and physiological processes, including lymphocyte trafficking, heart rate and rhythm, and vascular tone.1,2

S1P exerts its physiological actions by interacting with five G-protein coupled receptors (S1P1–5 receptors), which are variably expressed across different cell types, including lymphocytes, endothelial cells, atrial myocytes, and all cell types within the central nervous system.1,2

Sphingosine-1-phosphate (S1P) receptors

S1P1, S1P2 and S1P3 receptors are ubiquitously expressed, whereas S1P4 and S1P5 receptors are narrowly expressed, being mostly limited to lymphoid and haematopoietic tissues, the central nervous system, and in certain immune cells.3

S1P receptors are expressed across multiple cell types2

Lymphocytes

Lymphocytes

Endothelial cells

Endothelial cells

Atrial myocytes

Atrial myocytes

Nerve cells

Nerve cells

Explore the roles of the different S1P receptors

S1P1 receptor

The regulation of lymphocyte migration is one of the best characterised functions of the S1P pathway, which is mainly mediated by the interaction of S1P with the S1P1 receptor. S1P1 is the most widely expressed S1P receptor, being commonly found on endothelial cells and lymphocytes.3 The interaction of S1P to the S1P1 receptor is what drives the migration of lymphocytes from the spleen and lymphoid tissues into the systemic circulation.3,4 This migration of lymphocytes across the body is achieved through a S1P gradient, with the S1P concentration being substantially higher in the circulation than in lymphoid tissues and organs.2,4

S1P2 and S1P3 receptors

S1P2 and S1P3 mediate vascular, intestinal, bronchial, and bladder smooth muscle vasoconstriction. Modulation of the S1P2 receptor by S1P is hypothesised to have opposite functions to S1P1 modulation, with a pro-inflammatory role expected. Pharmacological agents targeting these receptors have been associated with side effects such as hypertension and renal ischaemia reperfusion injury.4

S1P4 receptor

S1P4 regulates immune system function by guiding cell migration and differentiation of specific immune cells. The interaction of S1P with S1P4 mediates immunosuppressive effects by inhibiting secretion of effector cytokines while increasing the production of the anti-inflammatory molecule IL-10. In addition, S1P4 expression on dendritic cells plays a role in regulation of Th17 cells and IL-27 production, thereby allowing regulatory T cells to suppress cytotoxic T (CD8+ T) cells. S1P4 receptor expression also enhances trafficking of neutrophils from inflamed tissues to the draining lymph node.4

S1P5 receptor

The S1P5 receptor plays a role within the immune system by helping to guide natural killer cells from the bone marrow and lymph nodes into tissues. This receptor also controls brain endothelial barrier function, tight junctions, and permeability. In addition, S1P5 decreases NFKB activation on brain endothelial cells by lowering expression of adhesion molecules, inflammatory chemokines, and cytokines.4

Characteristics and immune system effects of S1P1–5 receptors4

S1P receptor subtype S1P1 S1P2 S1P3 S1P4 S1P5
Expression B, T, and dendritic
cells, heart tissue,
neurons, endothelium		 Endothelium, heart
tissue, smooth muscle
vessels, tumoral cells,
lung fibroblasts		 Smooth muscle
vessels, edothelium,
heart tissue, lung
fibroblasts		 T cells, dendritic cells;
breast tumoral cells		 Natural killer cells,
endothelial cells,
oligodendrocytes
Clinical relevance Immune modulation,
bradycardia, tumour
maintenance,
theoretical breast
cancer prognosis		 Kidney injury, tumour
maintenance,
fibroblast contraction		 Hypertension, tumour
maintenance		 Immune modulation Immune modulation,
myelination
Immune system effects Lymphocyte and
dendritic cell migration		 B cell migration in the
follicle promoting the
local confinement of
germinal centre B cells		 Location of immature B
cells and progenitors
within the bone marrow		 Regulation of DC
function and Th17
differentiation, neutrophil
trafficking, inhibition of
effector cytokines,
secretion of IL-10		 Natural killer cell
trafficking
S1P receptor subtype S1P1 S1P2 S1P3 S1P4 S1P5
Expression B, T, and dendritic
cells, heart tissue,
neurons, endothelium		 Endothelium, heart
tissue, smooth muscle
vessels, tumoral cells,
lung fibroblasts		 Smooth muscle
vessels, edothelium,
heart tissue, lung
fibroblasts		 T cells, dendritic cells;
breast tumoral cells		 Natural killer cells,
endothelial cells,
oligodendrocytes
Clinical relevance Immune modulation,
bradycardia, tumour
maintenance,
theoretical breast
cancer prognosis		 Kidney injury, tumour
maintenance,
fibroblast contraction		 Hypertension, tumour
maintenance		 Immune modulation Immune modulation,
myelination
Immune system effects Lymphocyte and
dendritic cell migration		 B cell migration in the
follicle promoting the
local confinement of
germinal centre B cells		 Location of immature B
cells and progenitors
within the bone marrow		 Regulation of DC
function and Th17
differentiation, neutrophil
trafficking, inhibition of
effector cytokines,
secretion of IL-10		 Natural killer cell
trafficking

Adapted from Pérez-Jeldres T et al. 2021.4

The relevance of S1P in ulcerative colitis

The signalling molecule S1P generates a concentration gradient (low in the tissues and high in the blood) which helps to regulate biological processes such as inflammation and immune cell transport.2,4,5 In UC, where there is a state of chronic inflammation in the GI tract, the S1P concentration gradient is disrupted and the concentration of this signalling molecule is markedly elevated within the inflamed intestinal tissue.*4–6

This altered S1P concentration gradient contributes to the recruitment of immune cells from the lymphatic system and bloodstream into the inflamed tissue, driving persistent intestinal inflammation.1,2,5 In particular, S1P elevations in colitis have been shown to activate the transcription factor STAT3 and increase production of the cytokine IL-6, inducing a signalling cascade that upregulates the S1P1 receptor, ultimately driving lymphocyte migration into the inflamed intestine.1,3,5,6


*Based on a study in mice.6

What is ulcerative colitis (UC)?

UC is a chronic inflammatory condition of the GI tract that is thought to be mediated by a dysregulation of the immune system.5

Therapeutic potential of interfering with the S1P signalling pathway using S1P receptor modulators

Supraphysiological and pharmacological activation of the S1P1 receptor induces its internalisation, subsequent ubiquitination and proteasomal degradation. Consequently, the absence of the S1P1 receptor on the cell surface of lymphocytes prevents these cells from responding to the S1P gradient, causing their sequestration in peripheral lymphoid organs.1,2,4,5

Downregulation of the S1P1 receptor using small molecule S1P receptor modulators may limit the number of naïve and central memory T cells, B cells and autoreactive lymphocytes that traffic from the lymphoid organs into the inflamed intestine, potentially mitigating the ongoing inflammatory process in patients with UC.2,5

ZEPOSIA: A first-in-class, highly selective S1P receptor modulator licensed
for the treatment of patients with moderate-to-severe UC7,8

ZEPOSIA selectively binds with high affinity to S1P1 and S1P5 receptors, causing their internalisation and subsequent inhibition of lymphocyte migration along the S1P gradient to the inflamed tissue, contributing to reduced inflammation of the GI tract.1,2,7,8

ZEPOSIA mechanism of action in UC

ZEPOSIA does not affect the levels of circulating effector memory lymphocytes and has a minimal impact on cells involved in the innate immune response, allowing these cells to remain in the periphery and maintain immune surveillance.2,7


ZEPOSIA has minimal or no activity on S1P2, S1P3 and S1P4 receptors, which may help avoid off-target side effects in cells where these receptors are expressed.4,7

Explore the efficacy of ZEPOSIA in the TRUE NORTH study

DC, dendritic cell; GI, gastrointestinal; IL, interleukin; NFkB, nuclear factor kappa B; S1P, sphingosine-1-phosphate; Th, T helper; UC, ulcerative colitis.

References

  1. Dal Buono A et al. Biomedicines. 2022;10(7):1735.
  2. Scott FL et al. Br J Pharmacol. 2016;173(11):1778–1792.
  3. Danese S et al. J Crohns Colitis. 2018;12(suppl 2):S678–S686.
  4. Pérez-Jeldres T et al. Drugs. 2021;81(9):985–1002.
  5. Tourkochristou E et al. World J Gastroenterol. 2023;29(1):110–125.
  6. Suh JH, Saba JD. Transl Cancer Res. 2015;4(5):469–483.
  7. ZEPOSIA (ozanimod) Summary of Product Characteristics, 2023.
  8. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280–1291.

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Job: 2084-GB-2300319 Date of Preparation: November 2023