WO1997038696A1

WO1997038696A1 - Bisphosphonates as anti-inflammatory agents

Info

Publication number: WO1997038696A1
Application number: PCT/GB1997/001037
Authority: WO
Inventors: Anthony Robert Lyons; Sharon Patricia Mary Crouch; David James Phipps; Andrew Wilcock
Original assignee: The University Of Nottingham
Priority date: 1996-04-17
Filing date: 1997-04-15
Publication date: 1997-10-23
Also published as: GB9607945D0; AU2518697A; GB2312165A; GB9707570D0

Abstract

The use of a bisphosphonate, and in particular ibandronate (formerly known as BM21.0955) for the preparation of an agent for the treatment of diseases of chronic immune system activation and also for the preparation of an anti-inflammatory agent for the treatment of inflammatory disorders.

Description

Bisphosphonates as Anti-Inflammatory Anents

The present invention relates to bisphosphonates as anti-inflammatory agents, and particularly but not exclusively to ibandronate as an anti- inflammatory agent.

Diseases of chronic immune system activation, such as cancer, Multiple Sclerosis (MS) and Acquired Immune Deficiency Syndrome (AIDS) cause localised inflammation of body tissue. This inflammation is mediated by cells of the immune system, including lymphocytes and macrophages, producing biochemicals, such as cytokines (Interleukins, Tumour Necrosis Factor) at the diseased site. These biochemicals act as chemical signals which attract further cells to the site, resulting in inflammation and often associated symptoms such as severe pain.

One example of a disease causing chronic immune system activation is cancer, in which tumour associated macrophages are involved in tissue remodelling and inflammation, and through the action of a number of cytokines released thereby control neovascularisation, tumour growth and stroma formation. Macrophages are recruited from the circulation in response to chemotactic factors such as monocyte chemotactic protein 1 (MCP-1) released by the diseased tissue. Another member of the chemokine family is Interleukin-8 (IL-8), a neutrophil chemo-attractant. Secretion of this cytokine by tumour associated macrophages causes the influx of neutrophils, which cells are then capable of producing an accute inflammatory reaction through the release of proteinases and toxic oxygen metabolite. Neutrophils are also capable of the de novo biosynthesis of cytokines, in particular Interleukin-1 (IL- 1). Interleukin-1 induces biochemical and cellular changes characteristic of the types of inflammation and tissue remodelling observed in joint destruction diseases. Interleukin-1 has also been shown to be a potent agonist for lnterleukin-8 release from peripheral blood mononuclear cells. In addition to being a potent neutrophil chemotaxin lnterleukin-8 has also been shown to play a role in angiogenesis, and has been implicated in promoting tumour growth and metastases through neovascularisation. Conventionally, diseases of chronic immune system activation are frequently treated with systemic corticosteroids, cyclophosphamide or cyclosporin. The use of these amino suppressive drugs is complicated by adverse reactions including neutrophenia, lymphopenia, monocytopenia. In addition to a reduction in the number of these immune cells, their function is also decreased. Moderate side effects of these drugs include abdominal pain, nausea and vomiting. Devasting side effects of prolonged immunosuppressive therapies include infertility, aseptic necrosis, teratogenesis and vertebral collapse. In addition, prolonged use of these drugs frequently does not alter the course or eventual outcome of the disease; rather, they treat symptoms of relapse or exacerbation.

It is therefore an object of the present invention to provide an improved anti-inflammatory agent to thereby reduce inflammation in conditions of chronic immune system activation, and other inflammatory conditions such as rheumatoid arthritis.

According to the present invention there is provided the use of a bisphosphonate for the preparation of an agent for the treatment of chronic immune system activation disorders.

The invenuon also provides the use of a bisphosphonate for the preparation of an anti-inflammatory agent for the treatment of disorders.

According to a further aspect of the present invention there is provided the use of ibandronate for the preparation of an agent for the treatment of chronic immune system activation disorders.

According to a further aspect of the present invention there is provided the use of ibandronate for the preparation of an anti-inflammatory agent for the treatment of inflammatory disorders.

The invention further provides for the use of bisphosphonates to modulate immune cell activity, such as lymphoctye and macrophage cell activity. Preferably bisphosphonate is used to inhibit inflammatory agent production, such as cytokine production and desirably including Interleukin, such as Interleukin-1.

Preferably the bisphosphonate is used in vitro, and preferably comprises ibandronate.

A still further aspect of the present invention provides for the use of bisphosphonates, in particular ibandronate to inhibit pro-mflammatory cytokine production and/or activity.

The invention further provides a pharmaceutical composition comprising a bisphosphonate and a physiologically acceptable excipient or carrier.

The bisphosphonate preferably comprises ibandronate.

An embodiment of the present invention will now be described by way of example only, with reference to the accompanying drawings. The drawings all comprise graphs, showing:

Fig. 1 - the effect of ibandronate on TNF secretion (No LPS);

Fig. 2 - the effect of ibandronate on TNF secretion (lOpg/ml LPS);

Fig. 3 - the effect of ibandronate on IL-8 production : lOpg/ml LPS; and

Fig. 4 - the effect of ibandronate on IL-8 secretion (No LPS).

The present invention principally provides for the use of a bisphosphonate, and in particular ibandronate (formerly known as BM21.0955) for the preparation of an agent for the treatment of diseases of chronic immune system activation and also for the preparation of an anti-inflammatory agent for the treatment of inflammatory disorders.

Ten patients were identified with advanced metastatic prostate carcinoma and bone pain due to lesions deposited in the bone. From peripheral blood, mononuclear cells were extracted and cultured (using a well recognised standard technique) with or without the presence of bacterial lipopolysaccharide (LPS) - a potent stimulator of these cells. In addition, varying concentrations of ibandronate were also added to the culture medium.

At varying time points, the cell cutlures were analyzed for the production of Interleukin 1 (IL-1), Intereukin -1 receptor antagonist (IL-lra), Tumour Necrosis Factor (TNF), soluble TNF receptor inhibitor (sTNFRI) and lnterleukin-8 (IL-8). Ibandronate did not induce significant inhibition of IL-1 in the presence or absence of LPS. Neither was there a significant effect of ibandronate on IL- lra release.

Ibandronate was seen to inhibit the spontaneous production of TNF however in the presence of LPS there was only significant inhibition after 48 hours of culture which is at the limit for cell viability in this cutlure technique. (Figs. 1 and 2). Ibandronate inhibited IL-8 secretion in a concentration dependent fashion in the presence or absence of LPS. (Figs. 3 and 4). No effect was shown upon the secretion of soluble TNF receptor inhibitor (sTNFRI).

Ibandronate may act as an anti-inflammatory agent through its inhibitory effects upon IL-8. This may prevent recruitment and activation of inflammatory cells. IL-8 is a potent stimulator of angioneogenesis (new blood vessel formation) at tumour sites and this may be effective in controlling metastatic seeding or growth. No change in the response of the cells was noted when they were first stimulated with LPS. This would suggest that responses to infective processes may be unimpaired and inhibition of the cytokine response would not render subjects immunodefficient.

Ibandronate therefore appears to specifically target the TNF and Interleukin-8 pathway to inhibit the production of these pro-inflammatory cytokines, and since cytokines are fundamental to inflammation thereby obviate or mitigate chronic immune system activation inflammation. This not only provides for alleviation of symptoms of many chronic immune system activation disorders, such as cancer, MS and AIDS, but may also provide a basis for keeping such diseases in check or providing a complete cure. Ibandronate can also be used to treat other inflammatory diseases such as rheumatoid arthritis, and also to prevent metastases of cancer.

The clinical use of ibandronate has shown that it has minimal side effects, the only known side effect consisting solely of morning fever. Thus, the use of ibandronate in accordance with the present invention will not be associated with the adverse reactions associated with the conventional use of immune suppressants.

Thus, it will be appreciated that the use of bisphosphonates, and in particular ibandronate as an anti-inflammatory agent, and for the preparation of an agent for the treatment of chronic immune system activation disease, via the modulation of the activity and cytokine production of immune cells, including lymphocytes and macrophages offers many advantages over known drugs. Since activated macrophages, lymphocytes and pro-inflammatory cytokines are involved in the pathogenesis and generation of symptom burden in disease of chronic immune system activation, ibandronate provides effective treatment for these diseases and their symptoms.

It is to be appreciated that the use of bisphosphonates and in particular ibandronate, as agents to prevent or reduce inflammation caused by other disorders, such as arthritis, is within the scope of this invention. Further, the use of bisphosphonates, and particularly ibandronate to inhibit or prevent metastases in cancer conditions is also within the scope of this invention.

Whilst endeavouring in the foregoing specification to draw attention to those features of the invention believed to be of particular importance it should be understood that the Applicant claims protection in respect of any patentable feature or combination of features hereinbefore referred to and/or shown in the drawings whether or not particular emphasis has been placed thereon.

Claims

1. The use of a bisphosphonate for the preparation of an agent for the treatment of chronic immune system activation disorders.

2. The use of a bisphosphonate for the preparation of an anti-inflammatory agent for the treatment of disorders.

3. The use of ibandronate or an active derivative thereof for the preparation of an agent for the treatment of chronic immune system activation disorders.

4. The use of ibandronate or an active derivative thereof for the preparation of an anti-inflammatory agent for the treatment of inflammatory disorders.

5. The use of bisphosphonates to modulate immune cell activity, such as lymphoctye and macrophage cell activity.

6. The use of bisphosphonate as claimed in any preceding claim, in which bisphosphonate is used to inhibit inflammatory agent production, such as cytokine production.

7. The use of bisphosphonate as claimed in any preceding claim, in which the bisphosphonate inhibits Interleukin, such as Interleukin-1.

8. The use of bisphosphonate as claimed in any preceding claim, in which the bisphosphonate is used in vitro.

9. The use of bisphosphonate as claimed in claim 8, in which the bisphosphonate comprises ibandronate or an active derivative thereof.

10. The use of bisphosphonates, in particular ibandronate or an active derivative thereof to inhibit pro-inflammatory cytokine production and/or activity.

11. A pharmaceutical composition comprising a bisphosphonate and a physiologically acceptable excipient or carrier.

12. An anti-inflammatory agent comprising bisphosphonate.

13. A pharmaceutical composition as claimed in claim 11 or 12, in which the bisphosphonate comprises ibandronate or an active derivative thereof.

14. The use of bisphosphonate substantially as hereinbefore described with reference to the accompanying drawings.

15. The use of ibandronate or an active equivalent thereof as hereinbefore described with reference to the accompanying drawings.

16. A pharmaceutical composition as hereinbefore described with reference to the accompanying drawings.

17. An anti-inflammatory agent as hereinbefore described with reference to the accompanying drawings.

18. Any novel subject matter or combination including novel subject matter disclosed, whether or not within the scope of or relating to the same invention as any of the preceding claims.