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Title:  Peptide T and related peptides in the treatment of inflammation, including multiple sclerosis

United States Patent:  6,265,374

Inventors:  Andersen; Anders Jorgen (Kokkedal, DK); Aston; Roger (Wiltshire, GB); Carlen; Peter Louis (Ontario, CA); Doob; Penelope Reed (Ontario, CA); MacFadden; Douglas Kevin (Ontario, CA); Phipps; David James (Ontario, CA); Rathjen; Deborah (New South Wales, AU); Widmer; Fred (New South Wales, AU)

Assignee:  Advanced Immuni T, Inc. (Stonybrook, NY)

Appl. No.:  421845

Filed:  October 20, 1999


A method of treating inflammation in patients in need of such treatment by administering an effective amount of I-A-B-C-D-E-F-G-H-II (General Formula), wherein A is Ala, Gly, Val, Ser, Thr or absent, B is Ala, Gly, Val, Ser, Thr, or absent, C is Ser, Thr or absent, D is Ser, Thr, Asn, Glu, Arg, Ile, Leu or absent, E is Ser, Thr, Asp or absent, F is Ser, Thr, Asp or absent, G is Tyr or absent, H is Thr, Arg, Gly, Met, Met(O), Cys, Thr, Gly or absent and I is Cys or absent II is Cys, an amide group, an ester group or absent. At least one of the amino acids optionally is substituted by a monomeric or polymeric carbohydrate or derivative thereof, such substitution being accomplished through hydroxyl and/or amino acid and/or amido groups of the amino acids, and wherein the peptide composes at least 4 amino acid residues, and a pharmaceutically acceptable salt thereof.

Description of the Invention

The present invention relates, broadly to the treatment or prevention of inflammation, whether caused by bacteria, viruses and/or other infective agents, opportunistic infections (which may be consequent on an immunodepressed state, for example resulting from cancer or therapy, particularly cytotoxic drug therapy or radiotherapy) autoimmunity or otherwise. In particular embodiments, the invention relates to the prevention or treatment of neurodegenerative or demyelinating diseases such as HTLV-1-associated myelopathy (HAM), multiple sclerosis (MS) and symptoms or diseases in humans which are associated with chronic immune activation. The invention also relates to pharmaceutical compositions useful in such treatment and/or prevention and to certain active peptides per se.

Septic shock is an illustration of a disease involving inflammation. Many of the clinical features of Gram-negative septic shock may be reproduced in animals by the administration of lipopolysaccharide (LPS). The administration of LPS to animals can prompt severe metabolic and physiological changes which can lead to death. Associated with the injection of LPS is the extensive production of tumour necrosis factor alpha (TNF-.alpha.). Mice injected with recombinant human TNF develop piloerection of the hair (ruffling), diarrhoea and a withdrawn and unkept appearance, followed by death if sufficient amounts are given. Rats treated with TNF become hypotensive, tachypneic and die of sudden respiratory arrest (Tracey et al. 1986 Science 234, 470). Severe acidosis, marked haemoconcentration and biphasic changes in blood glucose concentration were also observed.

Histopathology of such rats revealed severe leukostatsis in the lungs, haemorraghic necrosis in the adrenals, pancreas and other organs and tubular necrosis of the kidneys. All of these changes were prevented if the animals were pretreated with a neutralizing monoclonal antibody against TNF.

The massive accumulation of neutrophils in the lungs of TNF-treated animals reflects the activation of neutrophils by TNF. TNF causes neutrophil degranulation, respiratory burst as well as enhanced neutrophil antimicrobacterial and anti-tumor activity (Klebanoff et al, 1996, J. Immunol. 136, 4220; Tsujimoto et al, 1986 Biochem. Biophys. Res. Commun. 137, 1094). Endothelial cells are also an important target for the expression of TNF toxicity. TNF diminishes the anticoagulant potential of the endothelium, inducing procoagulant activity and down-regulating the expression of thrombomodulin (Stern and Nawroth, 1986 J. Exp. Med. 163, 740).

TNF is a product of activated macrophages and is produced in response to infection and malignancy. It was first discovered in LPS-treated mice as a serum factor which caused the haemorraghic necrosis of transplanted tumour cells in culture (Carswell et al, 1975 PNAS 72, 3666; Helson et al, 1975, Nature 258, 731). Cachexia, which is characteristic of chronic exposure to TNF, it a common symptom of advanced malignancy and severe infection. It is characterized by abnormal lipid metabolism with hypertriglyceridaemia., abnormal protein and glucose metabolism and body wasting. Chronic administration of TNF and IL-1 in mice, rats and/or humans causes anorexia, weight loss and depletion of body lipid and protein within 7 to 10 days (Cerami et al, 1985, Immunol. Lett. 11, 173; Fong et al, 1989 J. Exp. Med. 170, 1627, Moldawer et al, Am. J. Physiol., 254 G450-G456, 1988; Fong et al, Am. J. Physiol. 256 R659-R665 (1989); McCarthy et al, Am. J. Clin. Nutr. 42 1179-1182, 1982). TNF levels have been measured in patients with cancer and chronic disease associated with cachexia. The results are inclusive since large differences in TNF levels have been reported. These may have been explicable by the short half-life of TNF (6 minutes), differences in TNF serum binding protein or true differences in TNF levels in chronic disease states.

TNF-.alpha. and IL-1, with their common functional activities such as pyrogenicity, somnogenicity and being mediators of inflammation, have been impacted in the pathology of other diseases associated with chronic inflammation. apart form toxic shock and cancer-related cachexia. TNF has been detected in synovial fluid in patients with both rheumatoid and reactive arthritis (Saxne et al, 1988, Arthrit. Rheumat. 31, 1041). Raised levels of TNF have been detected in renal transplant patients during acute rejection episodes (Maury and Teppo 1987, J. Exp. Med. 166, 1132). In animals, TNF has been shown to be involved in the pathogenesis of graft-versus-host disease in skin and gut following allogenic marrow transplantation.

Administration of a rabbit anti-murine TNF antibody was shown to prevent the histological changes associated with graft-versus-host disease and to reduce mortality (Piquet et al, 1987, J. Exp. Med. 166, 1220). TNF has also been shown to contribute significantly to the pathology of malaria (Clark et al, 1987, Am. J. Pathol. 129, 192-199). Further, elevated serum levels of TNF have been reported in malaria patients (Scuderi et al, 1986, Lancet 2, 1364-1365).

Multiple sclerosis (MS) is generally considered by many authorities to be a chronic inflammatory disease.

Both MS and HTLV-1 associated myelopathy (HAM) affect the central and the peripheral nervous systems and both may present clinically as a myelopathy affecting both the spinal nerves and the spinal myelinated nerve fibres.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and is the commonest chronic neurological disease of young adults. The incidence of MS and its pattern of distribution have been unchanged for decades. The disease remains essentially untreatable.

MS has always been regarded as a disease of the temperate zones and has a prevalence in the northern United States, Canada and Europe of 1:1000. The disease has a gender predilection of 1.5:1 (female:male).

MS usually affects multiple areas of white matter in the central nervous system (CNS), most frequently, the perventricular white matter, brainstem, spinal cord and the optic nerves. The primary process destroys myelin sheaths and eventually kills oligodendrocytes creating the characteristic plaque of MS.

The early development of the plaque is characterised by the development of perivascular inflammation followed by the migration of lumpnocytes, plasma cells and macrophages into the lesion. This is followed by astrocyte gloisis and the attempts of remyelination by oligodendrocytes. The plaque is surrounded by lumphocytes.

Although the aetiology of MS is still unknown, the focus of research efforts that have led to plausible hypotheses have been those of immune dysregulation including autoimmunity and genetic predisposition, both of which may play a role in the actual development of disease.

Multiple immunological abnormalities are reproducibly found in patients in the acute stage of the disease. The synthesis of immunoglobins, although normal in the periphery, is increased in the central nervous system and the antibodies produced have a characteristic banding pattern. The antigenic specificity of these antibodies is not known and it is unclear whether they have a role to play in the progression of disease.

Various stressors known to activate the immune system such as viral infection or surgery can also produce an exacerbation of MS. Other activators such as .gamma.-interferon produce similar effects when administered. In addition, immunosuppresive anti-inflammatory therapy with corticosteroids for example, can produce modest remission or at least palliation for short periods of time, although this therapy is controversial.

Lymphocyte reactivity against two neuronal antigens myelin basic protein and proteolipid has been demonstrated. Although not proven, this activity would form the basis for an autoimmune response against neuronal tissue.

The discovery of the neurotropic capacity of HTLV-1 in patients form Martinique with tropical spastic paraparesis (TSP) and in Japan with chronic myleopathy, has demonstrated HTLV-1 as the common aetiologic agent of these diseases. It has subsequently been shown that the neurologic manifestations of HTLV-1 infection are the same despite the varied geographic regions in which they are described.

The neurological signs of this chronic retroviral infection including slowly progressive spastic paraparesis with spastic bladder and minimal sensory deficits result form involvement of the pyramidal tracts in a bilateral and symmetrical fashion predominantly at the thoracic level of the spinal cord.

The peripheral nervous system has been shown to be involved, resulting in slowing of nerve conduction velocities in than lower limbs. Systemic manifestations of HTLV-1 in patients with HTLV-1 myelopathy have been described and include inflammatory involvement of the lungs, skin, eyes and striated muscle producing a myositis. In addition, patients experience profound fatigue similar to MS. The clinical manifestations of the disease are very similar to MS and are frequently confused with the latter.

There are at least four possible pathogenetic mechanisms whereby HTLV-1 can involve the CNS to produce HAM. These may include a slow virus infection, a cell-mediated immune response and a predominantly humoral immune mediated mechanism and the development of an autoimmune phenomenon. The slowly progressive course supports the hypothesis of a slow virus infection. The finding of peri-vascular cuffing in post-mortem specimens as well as transiently favourable response to steroids supports the hypothesis that an inflammatory immune reaction, probably a result of viral infection, is responsible for the development of HAM.

These two diseases have many similarities and dissimilarities, both clinical and neurological. Both diseases are a form of demyelinating disease whereby the myelin sheath of the nervous system is destroyed by one of many mechanisms common to both diseases and also peculiar to either of the diseases. MS is a multi-faceted disease in that can be both a central nervous system disease which can include a myelopathy. Conversely, HTLV-1-associated myelopathy is predominantly a myelopathy which can occasionally demonstrate central nervous system effects. Furthermore, MS can affect the peripheral nervous system in ways that are common HTLV-1.

Myelopathy, as already mentioned in being a disorder of the spinal cord, can have many different aetiologies from MS and HAM. Various forms of myelopathy, most of which are mediated by inflammation include the following:


B12 or folate deficiency;


transverse myelitis;


cervical spondylitis;

motor neuron disease;


spinal cord compression from tumour, disc or arthritis;

lupus erythematosus of the spinal cord; and

viral encephalomyelitis.

Chronic inflammation or, as more commonly known, chronic immune system activation occurs in response to persistent antigen whose origin may be exogenous or endogenous or may result from an autoimmune state. Such chronic inflammation results in local tissue destruction and depending upon the type of inflammation can result in systemic effects due to the sustained production of inflammatory mediators. Such inflammatory mediators include the cytokines which are soluble mediators produced by activated lymphocytes and macrophages and effect cellular communication and physiological response. Chronic immune activation can occur as a result of infectious diseases, such as chronic fatigue syndrome or toxic shock syndrome or through autoimmune mechanisms resulting in such conditions as rheumatoid arthritis, inflammatory bowel disease and variants such as graft versus host interactions.

The immune response to antigen may be divided into four overlapping phases: initiation (antigen presentation), amplification (cell activation), effector and regulation (Roitt et al, "Immunology", Gower Medical Publ. London. EK, 1989; "Basic and Clinical Immunology, Stites et al, Eds, Appleton and Lance, Norwalk, Conn., 1991). Briefly antigen is phagocytosed by antigen presenting cells (APC) which must express major histocompatibility (MHC) Class II molecules on their surface. In this respect, cells of the macrophage/monocyte lineage (CD4 positive) and B cells (CD4 negative) may act as APC. Following phargocytosis, antigen is processed intracytoplasmically and expressed on the surface as antigenic fragments in association with MHC-II molecules. The combination of antigen/MHC-II induces the activation of T helper cells (CD4 positive) in an antigen-specific manner and primes them to receive a second antigen non-specific activating signal. Activated T helper cells than induce the activation of effector T cells (cytoxic lymphocytes, CD4 negative) and B cells which produce antibody. Effector cells and molecules facilitate the elimination of antigen by a variety of antigen specific and non-specific mechanisms that may result in host tissue damage if effector mechanisms are expressed inappropriately by deposition of antigen or immune complexes on host tissues, responding to self-antigens or as a result of a prolonged (chronic) immune response. Regulation of the immune response via removal of antigen, active suppression or idiotypic regulation limits the normal immune response to a duration of one to three weeks.

Chronic fatigue syndrome (CFS) or chronic fatigues immune dysfunction syndrome (DeFritas et al, Proc. Natl. Acad. Sci. 88, 2922-2926 (1991)) is a condition of unknown aetiology characterised by a diverse set of signs and systems including severe fatigue, post-exertional malaise, headaches, night sweats, myalgia, ataxia, low grade fever and lymphadenophathy (CDWR 1-3: Joncas J H. Welcome and Introduction in: Proceedings of a Workshop: Chronic Fatigue Syndrome, Can. Dis. Weekly Report vol. 17S1E, January 1991 pages 1-3. ).

Although the origin of CFS is unknown its symptoms are consistent with over-production of cytokines (Landay et al, Lancet 338 707-712 (1991)). CFS-like symptoms have been observed following the therapeutic administration of interferons (INFs) (Lloyd et al, Med. J. Aust. 151 122-124 (1989); Lever et al, Lancet 2 101 (1988); Mowbray et al, Br. Med. Bull. 47 886-894 (1991)) and interleukin-2 (IL-2) (Cheney et al, Annal. Intern. Med. 110 321 (1989)). In a trial of IFN-.alpha. in patients with CFS, the drug exacerbated the condition further supporting a cytokine-mediated pathogenesis (McBride et al, Br. Med. Bull. 47 895-907 )1991)). The serum and cerebrospinal fluid of patients with CFS has been shown to contain increased levels of IL-2, IFN and IL-1 (Wallace et al, Arth. Rheum. 32 1334-1335 (1989); Shepperd The Practitioner 233 41-46 (1989)); as well as IL-6 (Chao et al, J. Infect. Dis. 162 1412 (1990)). In addition neopterin, a marker of machrophage activation (Chao et al, J. Infect. Dis. 162 1412 (1990)). and the IFN-associated enzyme 2'-5'-oligoadenylate synthetase (Klimas et al, J. Clin. Microbiol. 28 1403-1410 (1990)) are both incresed in CFS as are other markers of macrophage activation such as ICAM-1 and LFA-1 (Gupta et al, Scand. J. Immunol. 33 319-327 (1991)). CFS-associated anery to skin test antigens (Johnson et al. FASEB J. 5 2706-2712 (1991)), reduction in lymphocyte response to mitogens (Klimas et al, J. Clin. Microbiol. 28 1403-1410 (1990)) and soluble antigens (Gupta et al, Scand. J. Immunol. 33 319-327 (1991)) are consistent with macrophage dysfunction (Prieto et al, Scand. J. Immunol. 30 13-20 (1989)) and may be explained by an autocrine exhaustion of immunocompetent cells by chronic activation resulting in immunodysregulation (CDWR 1-3: Joncas J H, Welcome and Introduction in: Proceedings of a Workshop Chronic Fatigue Syndrome. Can. Dis. Weekly Report vol. 17S1E, January 1991, pages 49-50).

CFS and the acquired immune deficiency syndrome (AIDS, see below) share many symptoms (Miller et al, Neurology 41 1603-1607 (1991)) and laboratory findings (Gupta et al, Scand. J. Immunol. 33 319-327 (1991)); and one study has demonstrated an association between infection with the HIV related retrovirus HTLV-II and CFS (Gupta et al, Scand. J. Immunol. 33 319-327 (1991)).

There is no accepted drug therapy for CFS. There have been anecdotal reports of beneficial effects following administration of amantidine, monoamine oxidase inhibitors (ie phenelzine), fatty acid supplements (McBride et al, Br. Med. Bull. 47 895-907 (1991)) and 5-hydroxytryptophan (Caruso et al, J. Int. Med. Res. 18 201-209 (1990)) among others, but controlled studies have not demonstrated efficacy.

Toxic shock syndrome (TSS) is produced by a Staphylococcus aureus enterotoxin, toxic shock syndrome toxin-1 (TSST-1). TSST-1 belongs to a family of staphylococcal exterotoxins which are mitogenic for T cells expressing particular V.beta. genes (Kappler et al, Science 244 811-813 (1989)). As a result of their non-specific mitogenicity, staphylococcal enterotoxins can induce the proliferation of up to 20% of T-cells and have been called "superantigens" (Johnson et al, Sci. Am. 266 92-101 (1992)). Macrophages are required to present TSST-1 to T-cells (Poindexter et al, J. Infect. Dis. 151 65-72 (1985)); however, like other staphylococcal enterotoxins, TSST-1 does not require antigen processing for T-cell activation (Pontzezr et al, Proc. Natl. Acad. 88 125-128 (1991)). The native molecule binds outside the antigen binding cleft of MHC Class II molecules to a non-polymorphic region of the .beta. chain (Fraser Nature 339 221-223 (1989); Johnson et al, FASEB J. 5 2706-2712 (1991)).

The symptoms of TSS (such as fever, rash, hypotension, nausea, vomiting and diarrhoea) are consistent with over-activation of the immune system (Johnson et al, Sci. Am. 266 92-101 (1992)) and over-production of cytokines (Ikejima et al, J. Clin. Invest. 73 1312-1320 (1984); Micussan et al, Immunology 58 203-208 (1986)). These symptoms have been reproduced in animal models by the administration of tumour necrosis factor (TNF) (Miethke et al. J. Exp. Med. 175 91-98 (1992)). Massive immune activation of this nature could lead to exhaustion of immunocompetent cells and may explain the immunosuppression associated with enterotoxin shock (Langford et al, Infect. Immun. 22 62-68 (1978)) and in vitro enterotoxin-induced T-cell anergy (O'Hehir et al, Immunol. Lett. 30 163-170 (1991)).

Therapy of TSS involves immediate replacement of lost fluid to counter hypovolaemia. If the patient fails to respond to anti-staphylococcal antibiotics than steroid therapy (ie methylprednisone) may be required for those in severe shock (Todd, Drugs 39 856-861 (1990)).

Rheumatoid arthritis (Marrow et al, "Autoimmune Rheumatic Disease", Blackwell Scientific Publ. Oxford UK, Chapter 4, pp148-207 (1987)) is a disease characterised by chronic inflammation and erosion of joints that may affect up to 3% of the population, including children. Symptoms of rheumatoid arthritis include morning stiffness, swelling and pain upon motion in at least one joint and joint swelling. Non-specific symptoms including lethargy, anorexia and weakness as well as fever and lymphadenopathy (characteristic of immune activation) may antedate joint involvement. Extra-articular manifestations of rheumatoid arthritis include vasculitis, cataracts, uveitis, interstitial fibrosis, pericarditis and myocarditis, pheripheral neuropathy, myeloid deposits, chronic anaemia and subcutaneous and pulmonary nodules.

Genetic factors and infectious agents including bacteria, fungi, mycoplasmas and viruses have been associated with the development of rheumatoid arthritis. Mild rheumatoid arthritis may be treated with non-steroidal anti-inflammatory drugs while severe cases require sytemic coricosteroids, anti-metabolites or cytotoxic agents. Experimentally, anti-CD4 monoclonal antibodies have been used to treat rheumatoid arthritis (Horneff et al, Cytokine 3 266-267 (1991); Horneff et al, Arth. Rheum. 34 129-140 (1991) and Shoenfeld et al, Clin. Exp. Rheum. 9 663-673 (1991)).

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that fulfills some of the criteria of an autoimmune disease (Snook, Gur 31 961-963 (1990)). Inflammation and tissue damage involes the recruitment and activation of neutrophils, macrophages and lymphocytes (MacDermott et al, Adv. Immunol. 42 285-328 (1988)) which generate cytokines and proinflammatory molecules such as prostaglandins and leukotrienes (MacDermott. Mt. Sinai J. Med. 57 273-278 (1990)). As a result of chronic activation of immunocompetent cells, IL-1, IL-6 (Starter. Immunol. Res. 10 465-471 (1991); Fiocchi, Immunol. Res. 10 239-246 (1991)) and TNF-.alpha. (MacDermott, Mt. Sinai J. Med. 57 273-278 (1990)) are all elevated in IBD patients.

Drugs used to treat IBD include anti-inflammatory agents such as sulphasalazine (5-ASA), corticosteroids, cyclosporin A and azathioprine (Hanauer, Scand. J. Gastroenterol. 25 (Suppl 175) 97-106 (1990); Peppercorn, Annal. Intern. Med. 112 50-60 (1990)). Experimentally, anti-CD4 monoclonal antibodies have been used to successfully treat ulcerative colitis (Emmrich et al, Lancet 338 570-571 (1991)).

While a host may react against a genetically incompatible graft producing a host-versus-graft response, an immunocompetent graft (such as bone marrow or intestinal tissue) may react against the host resulting in graft-versus-host disease. These reactions are mediated by allogenic responses directed against, a foreign MHC molecule and are mimicked in vitro by the mixed lymphocyte reaction (MLR). Graft/host interactions result in chronic inflammation surrounding the grafted tissue with an increase in markers of immune activation such as are seen in AIDS (Grant, Immunol. Today 12 171-253. (1991)). Treatment of the graft/host interactions currently include either azathoprine, cyclosporin A or methylpredisone and more recently, rapamycin (Stepkowski et al, Transplantation 53 254-264 (1992); Huber et al, Bibliotheca Cardiologica. 43 103-110 (1988)). Monoclonal antibodies specific for CD3 (Wissing et al, Clin. Exp. Immunol. 83 333-337 (1991)) and CD4 (Reinke et al, Lancet 338 702-703 (1991)) have been used experimentally to inhibit graft/host reactions.

The present invention deals with the identification of a group of peptides that alleviates the inflammatory response in a number of diseases. These include: autoimmune disease, organ transplantation; neoplasia; viral, bacterial, fungal or other infections; and, in particular, any disease wherein infection can manifest in an opportunistic fashion, eg during cytotoxic or radiation therapy or in any situation where an immunodepressed state exists. Peptides useful in the present invention do not necessarily interfere directly with the pathogenic mechanisms of the disease-causing component. As will be described below in the experimental data, the mechanism whereby these peptides can alleviate the symptoms of these diseases is dependent on their capability of modulating the production and effect of cytokines produced by activated cells of the immune system. The modulation of cytokines may not be limited to TNF but may also be valid for a whole range of interleukins, for example from interleukin-1 to interleukin-10. The data presented are at present not direct evidence, but rather a powerful indirect model. Thus, the model uses one of the most powerful inflammatory compounds known, LPC, which binds to receptors on neutrophils, monocytes and macrophages; these cells consequently become activated and start production of IL-1 and TNF, among other cytokines, thus starting the inflammatory cascade. One parameter used to measure this effect of LPS is the concentration of blood glucose, which normally decreased on exposure to TNF or LPS. From what is known in the literature about the mechanism of Peptide T at a cellular level, it is therefore highly surprising that Peptide T and its analogues are able significantly to reduce the negative effects of LPS. LPS normally combines with LPS-Binding Protein (LBP) and exerts its dramatic effect through the CD14 receptor. In the literature up to date, the peptides useful in this invention have only been connected to the CD4 receptor, which is not believed to be involved in the primary inflammatory response associated with cytokines, such as TNF, or LPS.

More specifically, it has been discovered that a particular group of peptides, particularly those within the group having at least 5 amino acid residues, are very effective agents useful in the treatment, inter alis, MS and HAM, and are likely to be useful in treating other myelopathies, most of which have similar disease mechanisms.

From the above discussion, it is apparent that many symptoms and diseases are associated with chronic inflammation; however, several of these diseases appear to involve different mechanisms. It is therefore important that particular compounds have been found which are useful in treating symptoms and diseases associated with chronic inflammation where it appears that these compounds interact in some manner with CD4 receptors of immune system cells. The compounds relate, as indicated above, to Peptide T and its various derivatives. It was originally thought that such compounds had no effect on the immune system other than being very useful in blocking attachment of HIV virus to CD4 receptor cells (Ruff et al, IV Interantional Conference on AIDS, Stockholm June 1988).

Originally, many of the peptides useful in the invention were described as being effective in the prevention of infection and replication of HIV in vitro; see EP-A-0249390, EP-A-0249394 and WO-A-8809338, all of which are incorporated by reference to the maximum extent allowed by law, as are all other documents referred to in this specification. All compounds disclosed in these specifications are useful for the present invention. The original peptide has its basic point of origin in the octapeptide Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Tyr. It is called Peptide T because 50% of the amino acid residues are threonines. This peptide has been identified from a subregion of the human immune deficiency virus (HIV) external glycoprotein molecule gp120, which is responsible for binding to any cell carrying the CD4 molecule and, in particular, helper lymphocytes, microglial cells in the CNS, monocytes and dendritic cells. Binding occurs via specific attachment of gp120 the CD4 molecule. Treating individuals infected with HIV with this peptide and its derivatives, which are described below, consequently has the effect of potentially inhibiting binding of the whole virus or the neutotoxic gp120 molecule to the cell receptor CD4. In this way, the cell is protected from infection, and so the virus, being unable to replicate, is destroyed by the immune defence.

According to a first aspect of the present invention, there is provided the use of a linear or cyclic peptide of General Formula 1:

I-A-B-C-D-E-F-G-H-II General Formula 1) (SEQ. ID. NO: 1))

wherein A is Ala, Gly, Val, Ser, Thr or absent,

B is Ala, Gly, Val, Ser. Thr or absent,

C is Sef, Thr or absent,

D is Ser, Thr, Asn, Glu, Arg, Ile, Leu or absent,

E is Ser, Thz, Asp or absent,

F is Thr, Ser, Asn, Arg, Gln, Lys, Trp or absent,

G is Tyr or absent,

H is Thr, Arg, Gly, Met, Met (O), Cys, Thr, Gly or absent,

I is Cys or absent,

II is Cys or absent,

at least one of the amino acids optionally being substituted by a monomeric or polymeric carbohydrate or derivative thereof, such substitution being accomplished through hydroxyl and/or amino and/or amido groups of the amino acids.

and wherein the peptide comprises at least four amino acid residues,

or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing inflammation.

Each of the amino acids referred to in General Formula 1 may be in the L- or D- stereoisomeric configuration and candidates for H may be esterified or amidated. The peptide comprises at least 4 amino acids.

Tetra-, penta-, hexa-, hepta-, octa- and nona-peptides useful in the invention are all of the peptides chosen from the sequence:


by deleting residues, for example, one at a time, from either the carboxyl or amino terminal, or from within the sequence.

It is appreciated that peptides having the core sequence of Thr-Thr-Asn-Tyr-Thr- may have at both ends additional amino acid residues, some of which are represented by General Formula 2:

X-Ser-Thr-Thr-Thr-Asn-Tyr-Y (General Formula 2)(SEQ ID NO:2)

wherein X is an amino acid terminal residue selected from Ala and D-Ala and Y is a carboxy terminal residue selected from Thr and Thr-amide.

A particular preferred peptide of the group of peptides has the aforementioned core sequence of -Thr-Thr-Asn-Tyr-Thr -. These peptides of the above General Formula 2, and in particular a variant Peptide T of the formula -Ser-Thr-Thr-Thr-Asn-Tyr-, were found to be very useful in inhibiting binding of the human immunodeficiency virus (HIV) to human cells by blocking receptor sites on the cell surfaces. The term Peptide T is used throughout the specification to reference, unless the context otherwise requires, peptides of General Formula 2 which all include the core peptide sequence. It is therefore intended that Peptide T encompass all of the compounds of General Formula 2 where it is understood that all such compounds are variants of the normally understood octapeptide T, also referred to as prototype Peptide T, of the particular formula S-Ala-Ser-Thr-Thr-The-Asn-Tyr-Thr-amide (SEQ ID NO:3).

The invention may be useful in both clinical (human) and veterinary medicine. The invention therefore has application in a method for treating or preventing inflammation, the method comprising administering to a human or other animal subject, for example on a repeated basis, a peptide of General Formula 1. The peptide will generally be administered in an effective, non-toxic amount or in such an amount that strikes an acceptable balance between efficacy and toxicity, having regard to the circumstances of the case.

Preferred peptides useful in the invention have, as their active portion, an amino acid sequence of the formula:

-Thr-Thr-Asn-Tyr-Thr-(SEQ ID NO: 4).

These peptides, while being useful for all prophylactic and therapeutic utilities within the invention, are particularly preferred for the prevention or treatment of MS and HAM and for the prevention or treatment of symptoms or diseases, in humans or other animals, associated with chronic immune activation, chronic inflammation and chronic autoimmune disease.

Most preferred peptides useful in the invention, then, are the following:

1. D-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 (prototype Peptide T) (SEQ ID NO: 3)

2. Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 5)

3. D-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 3)

4. D-Ala-Ala-Ser-Ser-Ser-Asn-Tyr-Met (SEQ ID NO: 6)

5. Thr-Asp-Asn-Tyr-Thr (SEQ ID NO: 7)

6. Thr-Thr-Ser-Tyr-Thr (SEQ ID NO: 8)

7. Thr-Thr-Asn-Tyr-Thr (SEQ ID NO: 4)

8. D-Thr-Thr-Tyr-D-Thr (SEQ ID NO: 9)

9. D-Ala-Ser-D-Thr-Thr-D-Thr-Asn-Tyr-D-Thr-NH2 (SEQ ID NO: 10)

10. D-Ser-Ser-D-Thr-Thr-D-Thr-Thr-Tyr-D-Thr-NH2 (SEQ ID NO: 11)

Quite often it may be an advantage to have the amino terminal amino acid as a D-stereoisomer, to protect the molecule from degradation from aminopeptidases; alternatively or additionally, the carboxy terminal amino acid may be an amino acid amide to protect the molecule from degradation from carboxypeptidases. In this connection, compounds 5, 6 and 7, listed above, include analogues with D-Thr as the amino terminal residue and/or an amide derivative at the carboxy terminal.

Furthermore, it should be understood that one more of the amino acids in the peptides may be substituted N-alkyl (e.g. (C1 -C4) alkyl) amino acids instead of primary amino acids; examples include methyl and ethyl. The hydroxyl group side chains of one or more of the amino acids (Ser, Thr, Tyr) may be derivatised into an ether or ester group. Any (optionally substituted) alkyl ester or ether may be formed, such as (C1 -C4) alkyl, aryl or aryl (C1 -C4) alkyl esters, ethers, thioesters and thioethers, for example phenylester, benzylether or thiophenol ethylester. The presently preferred ethers are methyl, ethyl and propyl ethers and presently preferred esters are methyl, ethyl and propyl esters.

The hydroxyl side chains of the amino acids Ser, Thr and/or Tyr and the amido groups of the amino acids Asn and/or Gln may be substituted with different carbohydrates or derivatives of carbohydrates. Carbohydrate derivatives may be as discussed above.

Linear peptides useful in this invention may be prepared by any suitable process, such as conventional solid phase peptide synthetic techniques; see "Solid Phase Peptide Synthetic Techniques", 2nd ed, J. M. Stewart, J. D. Young.

Pierce Chemical Company, 1984, ISBN: 0-935940-03-0. A frequently used solid phase method is the Merrifield technique. Another possibility is solution phase techniques. The preferred peptide, prototype Peptide T, is readily obtainable from Carlbiotech A/S, Copenhagen, Denmark.

Cyclic peptides useful in the invention may be prepared by known techniques, such as, for example, described in Y. Hamada in Tetrahedron Letters, 26 5155 (1985). Cyclic peptides may be established in the form of a disulphide bridge between two Cys residues and/or by reacting the carboxy terminal amino acid residue with the amino terminal residue and/or by reacting the amino terminal residue with for example the .gamma.- carboxyl group of Glu, when Glu is at position D.

Carbohydrate derivatives may be prepared by methods known in the art.

Certain peptide derivatives useful in the invention are new and themselves form another aspect of the invention according to which there is provided a linear or cyclic peptide of General Formula 1:

I-A-B-C-D-E-F-G-H-II (General Formula 1)

wherein A is Ala, Gly, Val, Ser, Thr or absent,

B is Ala, Gly, Val, Ser, Thr or absent,

C is Ser, Thr or absent,

D is Ser, Thr, Asn, Glu, Arg, Arg, Ile, Leu or absent,

E is Ser, Thr, Asp or absent,

F is Thr, Ser, Asn, Arg, Gln, Lys, Trp or absent,

G is Tyr or absent,

H is Thr, Arg, Gly, Met, Met(O), Cys, Thr, Gly or

I is Cys or absent,

II is Cys or absent,

at least one of the amino acids being substituted by a monomeric or polymeric carbohydrate or derivative thereof, such substitution being accomplished through hydroxyl and/or amino and/or amido groups of the amino acids,

and wherein the peptide comprises at least four amino acid residues,

except for glycosylated prototype Peptide T,

or a pharmaceutically acceptable salt thereof.

Glycosylated Peptide T is disclosed in Urge et al., Biochem. Biophys. Res. Comms. 184(2) 1125-1132 (1992), published Apr. 30, 1992, but the utility of the present invention is neither disclosed nor suggested.

Preferred features of this aspect of the invention are as for the first aspect.

Peptides useful in the invention may be administered as a composition in conjunction with a pharmaceutically acceptable carrier.

In this way the peptides can be used in pharmaceutical compositions and compositions of matter for treating and preventing any disease or condition caused by an organism, compound or immune dysfunction that results in an inflammatory reaction of the immune system.

The peptides or peptide formulations may be used alone or in combination with any other pharmaceutically active compound, such as an anti-infective agent, for example an antibiotic and/or antiviral agent and/or antifungal agent, or another pharmaceutically active compound, such as an anti-neoplastic agent.

The peptides may be administered orally, bucally, parenterally, topically, rectally, vaginally, by intranasal inhalation spray, by intrapulmonary inhalation or in other ways.

In particular, the peptides according to the invention may be formulated for topical use, for inhalation with spray or powder, for injection (for example subcutaneous, intramuscular, intravenous, intra-articular or intra-cisternal injection), for infusion or for oral administration and may be presented in unit dose form in ampoules or tablets or in multidose vials or other containers with an added perservative. The compositions may take such forms as suspensions, solutions, or emulsions or gels in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder and/or lyophilised form for direct administration or for constitution with a suitable vehicle (e.g. sterile, pyrogen-free water, normal saline or 5% dextrose) before use. The pharmaceutical compositions containing peptides(s) may also contain other active ingredients such as antimicrobial agents, or preservatives.

The compositions may contain from 0.001-99% (w/v or, preferably, w/w) of the active material. Peptide T obtainable from Carlbiotech A/S is usually formulated and packaged in a sterile manner in 5% dextrose solution in multi-dose vials. It will be appreciated that the peptide may be packaged in other carriers, such as saline. Preferably, the concentration of peptide in each dose is in the order of 8.5 mg/ml for subcutaneous injection in one ml doses.

The compositions are administered in therapeutically or prophylactic effective does, i.e. 0.05-10000 mg of peptide per day, in particular 5-1000 mg per day. Very large doses may be used as the peptide according to the invention is non-toxic. However, normally this is not required. The dose administered daily of course depends on the degree of inflammation and inflammatory response.

For administration by injection or infusion of the compositions, the daily dosage, as employed for treatment of adults of approximately 70 kg of body weight, will often range from 0.2 mg to 20 mg of active material which may be administered in the form of 1 to 4 doses over each day, such dosage ranges depending upon the route of administration and the condition of the patient.

Compositions as described above may be prepared by mixing or otherwise bringing into association the ingredients.

The invention may be useful in the prevention or treatment of illness or medical conditions, particularly those involving inflammation, such as:

Viral, bacterial or drug-induced hepatitis or meningitis;

Rheumatoid, psoriatic, reactive, or osteo-arthritisor other arthritides;

Sepsis/septic shock;

Dermal inflammation;

ARDS (adult respiratory distress syndrome);

Graft rejection;

Inflammation secondary to the chemotherapy or radiotherapy of neoplastic disease.

The invention finds particular use in the prevention or treatment of MS, HAM and other inflammatory myelopathies (particularly those previously specifically mentioned) and/or symptoms or diseases in humans which are associated with chronic immune activation. More particularly, the invention is useful in treating chronic fatigue syndrome, toxic shock syndrome associated with Staphylococcus aureus infection, arthritis, inflammatory bowel disease and host-versus-graft response in transplant patients. Such efficacious results in the use of the above compounds is thought to be due, without being limited to any particular theory, to the immunosuppressive activities of these compounds in chronic inflammatory states.

In order to provide a guideline for the administration of and insight into the use of the peptides according to the invention, particularly the treatment of MS, myelopathies such as HAM and chronic inflammation, and the formulation of the compositions, the following is offered as a guide based on the extensive work already conducted in the use of peptide T for treating HIV infection.

Peptide T is an octapeptide homologous to a region of gp120, an HIV envelope glycoprotein, and to human vasoactive intestinal peptide (VIP). It was originally developed by Pert et al (EP-A-0249394), to block the binding of gp120 (an HIV envelope glycoprotein) and thus also block binding of HIV to CD4, the specific membrane-bound vial receptor, thereby blocking internalisation of the virus into the cell--a process necessary for viral replication. The CD4 molecule necessary for the entry of HIV into cells has been localised on the surface of lymphocytes, macrophages, microglial cells, neurons and numerous other cells. Binding of HIV to the CD4 receptor has been demonstrated to effect viral entry; and binding of free (non-viral related) gp120 has resulted in neuronal toxicity in both in vitro and in vivo studies.

The efficacy of Peptide T in reversing signs of HIV-induced dementia has been demonstrated in both the Peptide T Phase I clinical trial at the University of Southern California in Los Angeles and in the Phase II clinical trial at the Fenway Clinic in Boston. Both studies have demonstrated improvement in the HIV-induced neurocognitive impairment in patients with AIDS.

To date, the Peptide T/gp120/VIP homology has been used to explain at least two possible mechanisms of action of Peptide T. Firstly, that it competitively binds to CD4 (the known receptor for HIV) on human cell surfaces and competes with both HIV and gp120 for binding sites.

The binding of Peptide T and its analogues of General Formula 1, or more particularly General Formula 2, to CD4 could produce a blocking effect to prevent the binding of any other molecule capable of binding to that receptor; alternatively, or in addition, the binding of Peptide T to CD4 could induce a reaction similar to that caused by the endogeneous ligand.

CD4 is the differentiation antigen that defines the T lymphocyte subgroup of helper/inducer cells, but it is also present on a wide variety of cells including neurons, activated macrophages and B cells. CD4 is the predominant receptor for HIV and was originally thought to be necessary for cellular infection. Using the monoclonal antibody OKT4, Pert et al (Proc. Natl. Sci. U.S.A. 83 9254-9258 (1986); Pert et al (Clin. Neuropharmacol. 9(4) S198 (1986)) demonstrated the presence of this antigen throughout the human CNS and showed that it is present in highest concentration in the dentate gyrus, hippocampus, amygdala and deep cortex. This distribution was found to be similar to that found in other higher mammals. Peptide T and similar analogues were found to inhibit and binding of radiolabelled gp120 to rat hippocampal membranes and to do so in 0.1 nM concentrations.

Using Peptide T and the same analogues, Pert et al (Proc. Natl. Sci. U.S.A. 83 9254-9258 (1986); Pert et al (Clin. Neuropharmacol. 9(4) S198 (1986)) were able to demonstrate a reduction in the detectable levels of HIV reverse transcriptase when these peptides were present in an assay of HIV infectivity. A ninefold reduction of reverse transcriptase took place at 100 nM concentrations of Peptide T.

Since gp120 is not identical in all isolated strains of HIV, a comparison was made with nine different HIV isolates Pert et al (Clin. Neuropharmacol. 9(4) S198 (1986)). Significant homology was found between the isolates examined and Peptide T when comparison was made with the core pentapeptide. (Ruff et al. FEBS Lett. 211 17-22 (1987); Brenneman et al. Nature, 335 639-642 (1988); Brenneman et al, Drug Dev. Res. 15 361-369 (1988); Komisaruk et al, Annals of the NY Acad. Sci. 527 650-654 (1988); Buzy et al. The Lancet 22 Jul., 226-227 (1989)). This comparison has now been extended to over twenty isolates.

The inhibition of gp120 and HIV binding to CD4, as well as the demonstration of reduced infectivity of HIV in the presence of Peptide T and its analogues, provides one possible mechanism of action to explain the clinical effects of Peptide T. In this regard, Peptide T in sufficient concentration may prevent new cellular infection with HIV. Initial research in this area was focused on the CNS for two reasons: a high concentration of CD4 molecules was found on neurons and one of the major effects of HIV infection is the development of neurocognitive dysfunction. These fats are particularly important given that Peptide T is transported from the blood to the brain by an active, saturable transport system, while its exit is by diffusion only, (Barrera et al, Brain Res. Bull. 19 629-633 (1987)).

Although it is well accepted that HIV can infect not only lymphocytes but also neurons, it is difficult to ascribe the neurologic dysfunction seen in HIV patients to active CNS HIV infection, since only a small number of neurons are actively infected. It has been suggested that the neurological deficits seen in HIV injection may occur not only as a result of infection but also as a result of a viral "toxin", such as gp120. Brenneman et al, Nature 335 639-642 (1988)) found that purified gp120 from two isolates as well as recombinant gp120 produced significant neuronal cell death in cultures of mouse foetal hippocampal neurons. Neurotoxicity could be reduced by pretreatment with antibody to CD4 and was completely eliminated by VIP. Since mouse neurons cannot be infected with HIV, it is evident that neurotoxicity is gp120-induced and is not a result of viral entry or replication.

VIP (66, 67, 68, 69: TDNYT) and the core peptide (61-65: TTNYT) share the homologous sequence that binds CD4, and that is also found in isolates of the much larger gp120. Peptide T, when used in the same mouse hippocampal neuronal culture system, completely, antigonised the gp120-induced neurotoxicity, Brenneman et al, Drug Dev. Res. 15 361-369 (1988)). In addition, CSF from a patient with AIDS dementia produced substantial neurotoxicity in this system (4-49%) killing at 1:100,000 dilution). This effect was inhibited by Peptide T, Buzy et al, The Lancet, July 22, pp 226-227, (1989)). Normally gp120 is produced in vast excess of amounts required for viral replication; this excess gp120 may exert a neurotoxic effect far out of proportion to the number of microglial cells or neurons actively infected with HIV.

Peptide T may act as an agonist in addition to or even in the absence of its neuroprotective effects against viral infection and neurotoxicity. Direct agonist activity has been demonstrated in two ways. Ruff et al, (FEBS Lett. 211 17-22 (1987)) showed that peptide T and two analogues were potent agonists of human monocyte chemotaxis. Their rank order potency as chemotactic agents corresponded to their relative ability to inhibit both gp120 binding and HIV T cell infectivity.

As a further demonstration of the agonist activity of Peptide T, both Peptide T and VIP exert their cellular effects via the regulation of protein kinase C: Zorn et al, The Endoc. Society. Abstract (1989)). Agonist activity of Peptide T is thus implied by the production of a transmembrane signal that can influence the regulation of protein kinase C. It has also been demonstrated in six individual experiments, as part of the present invention, that Peptide T can down-regulate the enzyme p56lck, a tyrosine kinase linked to the cytoplasmic portion of membrane-bound CD4, thus implying that the binding of Peptide T to the CD4 molecule can produce a transmembrane signal.

Further evidence of Peptide T's potential VIP-like agonist activity is provided by results from experimental testing of the hypothesis of Komisaruk et al, Annals of the NY Acad. Sci. 527 650-654 (1988) that VIP released from pelvic nerve terminals into the spinal cord can produce analgesia. Knowing that naloxone-independent analgesia produced by administration of VIP to the periaqueductal grey matter in rats had been shown, the investigators administered VIP directly to rat spinal cord and measured the pain threshold to distal noxious stimuli to test the hypothesis. Spinal administration of VIP produced analgesia as measured by the tail-flick latency response and the tail-shock induced vocalisation test by action on both opiate and non-opiate modulated pain pathways, Komisaruk et al, Annals of the NY Acad. Sci. 527 650-654 (1988)).

The existence of clinical benefits from the administration of Peptide T to humans has been suggested in all studies to data: in HIV disease, by the Pilot Swedish Study, the USC Phase I and Fenway/CRI studies, and the Toronto Western Hospital Compassionate Use Program involving 51 patients; in psoriasis and other medical conditions, in case reports from Sweden (Marcusson, Lazega et al, 1989-9, and Marcusson and Wetterberg, 189-10) and in 8 patients with psoriasis or other medical conditions in Toronto.

Neuroncognitive improvement found in HIV positive patients and improvement in constitutional symptoms in both HIV positive and HIV negative patients may well depend primarily on Peptide T's VIP-like neurotropic and agonist effects, as well as the anti-inflammatory and anti-TNF effects discussed below.

Not wishing to be bound by any particular theory, with respect to the use of these peptides with treatment of MS and HAM, and in view of the above guidelines and discussions in relation to the use of various peptides of General Formula 2 and their analgoues in the treatment of HIV, it is hypothesised that there are numerous similarities of disease expression and potential similarities of disease etiology. Peptide T appears to act as an agonist and as a blocker of CD4-mediated immune function rather than as an antiviral drug. In investigations associated with the present invention, patients with non-HIV disease such as multiple sclerosis, HTLV-1 associated myelopathy, and psoriasis have all been treated with Peptide T.

Now that the effectiveness of the peptides of General Formula 1, and particularly those of General Formula 2, is shown, the following is suggested as a hypothesis as to why the compounds do work:

1) Both HAM and MS are chronic CNS inflammatory and demyelinating diseases as is HIV disease.

2) Both diseases have possible viral aetiologies; it is now generally accepted that HAM is caused by the retrovirus, HTLV-1, a virus in the same family as HIV; MS has also been suggested as a manifestation of HTLV-1 infection and the chronic fatigue syndrome has recently been linked to a number of possible viral infections both of DNA (e.g. HHV-6) and retroviral aetiologies.

3) The two diseases share a number of common symptoms, for example, fatigue, lack of balance and signs of autoimmune phenomena; it is worth while noting that HTLV-1 disease exhibits numerous signs of autoimmunity such that it may be expected that some retroviral diseases have a concomitant expression in autoimmune phenomena. One common theme among these diseases may be peripheral neuropathy which is based on the process of demyelination.

4) The basis appears to be the common denominator of both demyelination whether it be in the central or peripheral nervous system and the common autoimmune manifestations in HAM, MS and HIV disease.

5) Demyelination is associated with inflammation of any aetiology and appears to be mediated at least in part by TNF.

Not wishing to be bound by any particular theory with respect to the use of peptides with the treatment of symptoms and diseases associated with chronic immune activation, and in view of the above guidelines and discussions in relation to the use of various peptides of General Formula 2 and their analogues in the treatment of HIV, it is hypothesised that there is an immunomodulatory effect of the Peptide T binding to CD4. Such effect is demonstrated in the following examples where Peptide T has been found to inhibit mitogen induced proliferation of peripheral blood mononuclear cells (PBMC) at picomolar and lower concentrations. We have found that Peptide T allowed PBMC to proliferate in response to mitogen, but at a reduced level compared to the growth of PMBC in its absence. Pre-incubation of PBMC with Peptide T for less than 30 minutes had no effect on mitogen stimulation. However, exposure of PBMC to Peptide T for 2 hours followed by washing of the cells before exposure to the mitogen resulted in inhibition of proliferation similar to that seen when cells are incubated in the presence of both Peptide T and mitogen. It was also found that Peptide T did not significantly affect the growth of PBMC cultured in the absence of mitogen. It is therefore thought that Peptide T is able to suppress the normal proliferative response of PBMC to non-CD4 associated proliferation signals.

Now that the effectiveness of the peptides of General Formula 1, and particularly those of General Formula 2, in treating symptoms and diseases associated with chronic immune activations or chromic inflammation has been discovered, the following is suggested as hypothesis of the mechanism of action of Peptide T and, therefore, why the compounds useful in the invention are effective.

Peptide T binds to CD4. It has been established in the following tests that peptide T inhibits mitogen and MLR induced lymphocyte proliferation. It is therefore thought that Peptide T may serve as an immunomodulatory drug which would down-regulate the enhanced immune response occurring in the chronic presence of antigen or for other reasons mentioned and hence reduce chronic inflammation.

Underlying all these utilities runs the common theme of inflammation.

In accordance with various embodiments of this invention and in view of the above guidelines gained from the use of peptides of General Formula 1, and particularly those of General Formula 2, in the treatment of HIV, similar doses of Peptide T and its analogues can be administered to humans or other animals for purposes of treating inflammation.

Claim 1 of 17 Claims

What is claimed is:

1. A method for treating or preventing inflammation in a subject by administering an effective amount of the peptide:

I-A-B-C-D-E-F-G-H-II (General Formula I)


A is Ala, Gly, Val, Ser, Thr or absent,

B is Ala, Gly, Val, Ser, Thr or absent,

C is Ser, Thr or absent,

D is Ser, Thr Asn, Glu, SArg, Ile, Leu or absent,

E is Ser, Thr, Asp or absent,

F is Thr, Ser, Asn, Arg, Gln, Lys, Trp or absent,

G is Tyr or absent,

H is Thr, Arg, Gly, Met, Met(O), Gys, Thr, Gly or absent,

I is Cys or absent,

II is Cys, an amide group, an ester group or absent,

at least one of the amino acids optionally being substituted by a monomeric or polymeric carbohydrate or an alkyl ester or alkyl ether derivative thereof, such substitute being accomplished through hydroxyl and/or amino groups of the amino acids, and wherein the peptide comprises at least 4 amino acid residues, or a pharmaceutically acceptable salt thereof.

If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.



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