Anti-IL-8 antibody ameliorates inflammation and fibrosis: A promising treatment for endometriosis

New study shows potential therapy for endometriosis-related pain and inflammation

Key Points

Highlight

• The newly developed long-lasting antibody, AMY109, targets interleukin-8 (IL-8) and reduces the volume of nodules and adhesions in monkeys with surgically induced endometriosis.

Importance

• IL-8 plays a crucial role in the progression of endometriosis by augmenting infiltration and activating immune cells.

What’s done here

• A team of researchers from Japan evaluated the efficacy and safety of anti-IL-8 on monkeys with surgically induced spontaneous developed endometriosis.
• The mRNA expression of inflammation-related genes in endometriotic tissues and identified cells that respond to IL-8 were analyzed.
• The effect of AMY109 on nodular lesions, adhesions, and fibrosis was evaluated
• The role of IL-8 and monocyte chemoattractant protein-1 (MCP1) in promoting fibrosis was investigated. 

Key results

• AMY109 induced atrophic changes in the nodular lesions and reduced the volume of the nodules.
• Postsurgical adhesions at the incisions were markedly reduced, by inhibiting IL-8, it reduced fibrosis and adhesions.
• It prevented neutrophils from being attracted to endometriotic lesions and stopped them from producing MCP1.

Lay Summary

Endometriosis is a condition associated with chronic inflammation and fibrosis, and there are limitations and side effects with current treatments such as hormonal therapy and surgery. Interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP1) are inflammatory cytokines that play a crucial role in the progression of endometriosis by augmenting infiltration and activating immune cells.

In an effort to create a disease-modifying drug, a team of researchers from Japan, led by Nishimoto-Kakiuchi, developed a long-lasting antibody that targets IL-8 called AMY109 and evaluated the efficacy and safety of this drug on monkeys with endometriosis, using both a surgically induced model and spontaneous development of the disease. They created a surgical method to induce endometriosis in female cynomolgus monkeys by transplanting endometrial tissues, which showed similarities to spontaneously developed endometriosis in humans and monkeys. The results were published in the February 2023 edition of the journal Science Translational Medicine.

The researchers analyzed the mRNA expression of 249 inflammation-related genes in endometriotic tissues compared to eutopic endometria of women without endometriosis. IL-8 was found to be the most up-regulated gene in endometriotic tissues, and its protein concentration was higher in cyst fluid than in plasma. The study also identified cells that respond to IL-8, including neutrophils, macrophages, and mononuclear cells. Fibrosis was observed in some endometriotic lesions, which had a distinct composition compared to lesions with inflammation characterized by columnar endometrial-like epithelium, thick stromal cell layers, bleeding, and angiogenesis.

It was seen that AMY109 induced atrophic changes in the nodular lesions and reduced the volume of the nodules, demonstrating its efficacy in inhibiting IL-8. Postsurgical adhesions at the incisions were also markedly reduced in AMY109-treated monkeys. IL-8 induced the expression of MCP1 protein in neutrophils, which in turn stimulated macrophages to migrate and secrete TGFβ1. However, AMY109 did not prevent macrophage-dependent augmentation of microtissue formation or the enhanced ability of fibroblast cell lines to contract collagen gel induced by the addition of macrophages.

What is more, monthly subcutaneous injections of AMY109 into monkeys with surgically induced endometriosis reduced the volume of the lesions and diminished fibrosis and adhesions. It was also found that IL-8 attracts neutrophils and induces the production of MCP1/CCL2, which triggers the migration of macrophages to lesions that promote fibrosis. However, it was seen that AMY109 did not directly affect macrophages. Instead, it inhibited IL-8, which in turn reduced fibrosis and adhesions.

The authors suggest that AMY109 may require a longer treatment duration than hormonal drugs, as fibrosis and adhesions develop as consequences of chronic inflammation triggered by menstrual bleeding.

Research Source: https://pubmed.ncbi.nlm.nih.gov/36812343/