WO2000018798A1 - Peptide antifongique et antibacterien - Google Patents

Peptide antifongique et antibacterien Download PDF

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Publication number
WO2000018798A1
WO2000018798A1 PCT/US1999/022277 US9922277W WO0018798A1 WO 2000018798 A1 WO2000018798 A1 WO 2000018798A1 US 9922277 W US9922277 W US 9922277W WO 0018798 A1 WO0018798 A1 WO 0018798A1
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Prior art keywords
xmp
seq
bpi
agents
set forth
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PCT/US1999/022277
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English (en)
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Roger G. Ii Little
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Xoma Technology Ltd.
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Priority to AU61630/99A priority Critical patent/AU6163099A/en
Publication of WO2000018798A1 publication Critical patent/WO2000018798A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4742—Bactericidal/Permeability-increasing protein [BPI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates generally to peptides derived from or based on Domain HI (amino acids 142-169) of bactericidal/permeability-increasing protein (BPI) and therapeutic uses of such peptides.
  • BPI is a protein isolated from the granules of mammalian polymorphonuclear leukocytes (PMNs or neutrophils), which are blood cells essential in the defense against invading microorganisms.
  • PMNs or neutrophils mammalian polymorphonuclear leukocytes
  • SEQ ID NOS: 2 and 3 have been reported in Figure 1 of Gray et al., J. Biol. Chem., 264:9505 (1989), incorporated herein by reference.
  • Recombinant human BPI holoprotein has also been produced in which valine at position 151 is specified by GTG rather than GTC, residue 185 is glutamic acid (specified by GAG) rather than lysine (specified by AAG) and residue 417 is alanine (specified by GCT) rather than valine (specified by GTT).
  • GTG asexual growth factor
  • GCT valine
  • GTT valine
  • Fungi are eukaryotic cells that may reproduce sexually or asexually and may be dimorphic. Fungi are not only important human and animal pathogens, but they are also among the most common causes of plant disease.
  • Fungal infections are becoming a major concern for a number of reasons, including the limited number of antifiingal agents available, the increasing incidence of species resistant to known antifiingal agents, and the growing population of immunocompromised patients at risk for opportunistic fungal infections, such as organ transplant patients, cancer patients undergoing chemotherapy, burn patients, AIDS patients, or patients with diabetic ketoacidosis.
  • the incidence of systemic fungal infections increased 600% in teaching hospitals and 220% in non-teaching hospitals during the 1980's.
  • the most common clinical isolate is Candida albicans (comprising about 19% of all isolates). In one study, nearly 40% of all deaths from hospital-acquired infections were due to fungi. [Sternberg, Science, 266: 1632-1634 (1994).].
  • BPI protein products are described in U.S. Patent No. 5,627,153 and corresponding International Publication No. WO 95/19179
  • Gram-positive bacteria have a typical lipid bilayer cytoplasmic membrane surrounded by a rigid cell wall that gives the organisms their characteristic shape, differentiates them from eukaryotic cells, and allows them to survive in osmotically unfavorable environments.
  • This cell wall is composed mainly of peptidoglycan, a polymer of N-acetylglucosamine and N-acetylmuramic acid.
  • the cell walls of gram- positive bacteria contain teichoic acids which are anchored to the cytoplasmic membrane through lipid tails, giving rise to lipoteichoic acids.
  • the various substituents on teichoic acids are often responsible for the biologic and immunologic properties associated with disease due to pathogenic gram-positive bacteria.
  • Most pathogenic gram-positive bacteria have additional extracellular structures, including surface polysaccharides, capsular polysaccharides, surface proteins and polypeptide capsules.
  • Gram-negative bacteria also have a cytoplasmic membrane and a peptidoglycan layer similar to but reduced from that found in gram-positive organisms.
  • gram-negative bacteria have an additional outer membrane that is covalently linked to the tetrapeptides of the peptidoglycan layer by a lipoprotein; this protein also contains a special lipid substituent on the terminal cysteine that embeds the lipoprotein in the outer membrane.
  • the outer layer of the outer membrane contains the lipopolysaccharide (LPS) constituent.
  • LPS lipopolysaccharide
  • BPI protein products have been shown to have additional antimicrobial activities.
  • U.S. Patent No. 5,646,114 and International Publication No. WO 96/01647 (PCT/US95/08624), all of which are incorporated by reference herein, disclose activity of BPI protein products against protozoa.
  • PCT/US95/08624 PCT/US95/08624
  • new antimicrobial methods and materials including, for example, those that target animal and plant pathogens.
  • effective antifiingal therapy for systemic mycoses is limited. Products and methods responsive to this need would ideally involve substantially non-toxic compounds available in large quantities by means of synthetic or recombinant methods.
  • Ideal therapeutic compounds would have a rapid effect upon systemic and/or oral administration, high potency, low toxicity, and a broad spectrum of activity against a variety of different microbes when administered or applied as the sole agent. Ideal compounds would also be useful in combinative therapies with other antimicrobial agents, particularly where these activities would reduce the amount of other antimicrobial agent required for therapeutic effectiveness, enhance the effect of such agents, or limit potential toxic responses and high cost of treatment.
  • Domain I is defined as the amino acid sequence of BPI comprising from about amino acid 17 to about amino acid 45. Initial peptides based on this domain were moderately active in both the inhibition of LPS-induced LAL activity and in heparin binding assays, and did not exhibit significant bactericidal activity.
  • Domain II is defined as the amino acid sequence of BPI comprising from about amino acid 65 to about amino acid 99. Initial peptides based on this domain exhibited high LPS and heparin binding capacity and exhibited significant antibacterial activity.
  • Domain III is defined as the amino acid sequence of BPI comprising from about amino acid 142 to about amino acid 169.
  • Initial peptides based on this domain exhibited high LPS and heparin binding activity and exhibited surprising antimicrobial activity, including antifiingal and antibacterial (including, e.g., anti-gram-positive and anti-gram-negative) activity.
  • the biological activities of peptides derived from or based on these functional domains may include LPS binding, LPS neutralization, heparin binding, heparin neutralization or antimicrobial activity.
  • the present invention provides a novel peptide, designated XMP.445, derived from or based on Domain III (amino acids 142-169) of bactericidal/permeability- increasing protein (BPI) and therapeutic uses of this peptide, especially as an antifiingal agent.
  • the sequence of XMP.445 is set forth in SEQ ID NO: 1.
  • the peptide, or pharmaceutical compositions comprising the peptide and suitable diluents, adjuvants or carriers may be administered alone or concurrently with other known antimicrobial (particularly antifiingal) agents.
  • the peptide may reduce the amount of the other agent needed for effective therapy, enhance the effect of such other agent, accelerate the effect of such other agent, or reverse (e.g., overcome) resistance of the pathogenic organism to such other agent.
  • the peptide may be effective for treating animals (e.g., mammals) in vivo, for treating plants, and for a variety of in vitro uses such as to decontaminate fluids and surfaces and to sterilize surgical and other medical equipment and implantable devices, including prosthetic joints and indwelling invasive devices.
  • animals e.g., mammals
  • in vitro uses such as to decontaminate fluids and surfaces and to sterilize surgical and other medical equipment and implantable devices, including prosthetic joints and indwelling invasive devices.
  • a further aspect of the invention involves use of the peptide for the manufacture of a medicament for treatment of microbial infection, e.g., fungal or bacterial infection.
  • the medicament may additionally include other chemotherapeutic agents such as antimicrobial agents.
  • the present invention provides a novel peptide designated XMP.445 (SEQ ID NO: 1) which consists of amino acid residues 150 through 161 (Lys-Val-Gly-Trp-Leu-
  • XMP.445 has been demonstrated to possess antifiingal activity in a variety of in vitro killing assays and in vivo models of fungal infection, including, for example, by measuring improved host survival or a reduction of colony-forming units in organs after fungal challenge.
  • XMP.445 Other properties of XMP.445, such as serum stability, oral absorption, and effect on fungal cells treated with a membrane potential indicator dye that localizes to mitochondria, were also determined. XMP.445 was observed to exhibit a spectrum of superior properties, including high potency and a broader therapeutic range in vivo, in one or more of the preceding assays in comparison to other peptides derived from or based on Domain III of BPI ("Domain III derived peptides").
  • the invention also provides methods of using XMP.445 for treating a subject suffering from infection (including fungal, bacterial, or other microbial infection), especially mammalian subjects such as humans, but also including farm animals such as cows, sheep, pigs, horses, goats and poultry (e.g., chickens, turkeys, ducks and geese), companion animals such as dogs and cats, exotic and/or zoo animals, and laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters.
  • infection including fungal, bacterial, or other microbial infection
  • farm animals such as cows, sheep, pigs, horses, goats and poultry (e.g., chickens, turkeys, ducks and geese)
  • companion animals such as dogs and cats
  • exotic and/or zoo animals e.g., mice, rats, rabbits, guinea pigs, and hamsters.
  • Immunocompromised or immuno suppressed subjects e.g., subjects suffering from cancer, subjects undergoing radiation therapy and/or cytotoxic chemotherapy, subjects being treated with immunosuppressive drugs, and subjects suffering from natural or acquired immune deficiencies such as AIDS, may be treated according to this aspect of the invention. Treatment of infection of plants is also contemplated. "Treatment” as used herein encompasses both prophylactic and therapeutic treatment, and may be accompanied by concurrent administration of other antimicrobial agents, including any of the agents discussed herein.
  • Fungal infection may be caused by a variety of fungal species including, e.g., species of Candida (including C. albicans, C. tropicalis, C. parapsilosis, C. stellatoidea, C. krusei, C. parakrusei, C. lusitanae, C. pseudotropicalis, C. guilliermondi and C. glabrata), Aspergillus (including A. fumigatus, A. flavus, A. niger, A. nidulans,
  • Candida including C. albicans, C. tropicalis, C. parapsilosis, C. stellatoidea, C. krusei, C. parakrusei, C. lusitanae, C. pseudotropicalis, C. guilliermondi and C. glabrata
  • Aspergillus including A. fumigatus, A. flavus, A. niger, A. n
  • Bacterial infection may be caused by gram-negative bacterial species, including Acidaminococcus, Acinetobacter, Aeromonas, Alcaligenes, Bacteroides, Bordetella, Branhamella, Brucell , Calymmatobacterium, Campy lobacter, Cardiobacterium, Chromobacte ⁇ um, Citrobacter, Edwardsiella, Enterobacter, Escherichia, Flavobacterium, Francisella, Fusobacterium, Haemophilus, Klebsiella, Legionella, Moraxella, Morganella, Neisseria, Pasturella, Plesiomonas, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Streptobacillus, Veillonella, Vibrio, and Yersinia species, or gram-positive bacterial species, including Staphylococcus, Streptococcus, Micrococcus, Pe
  • microbial infections may be caused by, e.g., protozoa, including Plasmodia, Toxoplasma, Leishmania, Trypanosoma, Acanthamoeba, Nagleria, and Pneumocystis species.
  • endotoxin such as exposure to gram- negative bacterial endotoxin in circulation, endotoxemia, bacterial and/or endotoxin- related shock and one or more conditions associated therewith, including a systemic inflammatory response, cytokine overstimulation, complement activ
  • compositions of the peptide may include a pharmaceutically acceptable diluent, adjuvant, or carrier.
  • the BPI protein product may be administered without or in conjunction with known surfactants, other chemotherapeutic agents or additional known antimicrobial agents.
  • known surfactants such as sodium sulfate, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium
  • Systemic routes of administration include oral, intravenous, intramuscular or subcutaneous injection (including into depots for long-term release), intraocular or retrobulbar, intrathecal, intraperitoneal (e.g. by intraperitoneal lavage), intrapulmonary (using powdered drug, or an aerosolized or nebulized drug solution), or transdermal.
  • Topical routes include administration in the form of salves, creams, jellies, ophthalmic drops or opthalmic ointments, ear drops, suppositories, such as vaginal suppositories, or irrigation fluids (for, e.g., irrigation of wounds).
  • Suitable dosages include doses ranging from 1 ⁇ g/kg to 100 mg/kg per day and doses ranging from 0.1 mg/kg to 20 mg/kg per day.
  • BPI protein product compositions are generally injected in doses ranging from 1 mg/kg to 100 mg/kg per day, preferably at doses ranging from 0.1 mg kg to 20 mg/kg per day, and more preferably at doses ranging from 1 to 20 mg/kg/day.
  • the treatment may continue by continuous infusion or intermittent injection or infusion, or a combination thereof, at the same, reduced or increased dose per day for as long as determined by the treating physician.
  • BPI protein product compositions When given topically, BPI protein product compositions are generally applied in unit doses ranging from 1 mg/mL to 1 gm/mL, and preferably in doses ranging from 1 mg/mL to 100 mg/mL.
  • Conscurrent administration or “co-administration,” as used herein includes administration of one or more agents, in conjunction or combination, together, or before or after each other.
  • the agents may be administered by the same or by different routes. If administered via the same route, the agents may be given simultaneously or sequentially, as long as they are given in a manner sufficient to allow all agents to achieve effective concentrations at the site of action.
  • a BPI protein product may be administered intravenously while the second agent(s) is(are) administered intravenously, intramuscularly, subcutaneously, orally or intraperitoneally.
  • a BPI protein product and a second agent(s) may be given sequentially in the same intravenous line or may be given in different intravenous lines.
  • a BPI protein product may be administered in a special form for gastric delivery, while the second agent(s) is(are) administered, e.g., orally.
  • Known antifiingal agents include polyene derivatives, such as amphotericin B (including lipid or liposomal formulations thereof) and the structurally related compounds nystatin and pimaricin; flucytosine (5-fluorocytosine); azole derivatives (including ketoconazole, clotrimazole, miconazole, econazole, butoconazole, oxiconazole, sulconazole, tioconazole, terconazole, fluconazole, itraconazole, voriconazole [Pfizer] and
  • SCH56592 [Schering-Plough]); allylamines-thiocarbamates (including tolnaftate, naftifine and terbinafine); griseofulvin; ciclopirox; haloprogin; echinocandins (including MK-0991 [Merck]); and nikkomycins.
  • antifiingal agents are a class of products related to bactericidal/permeability-increasing protein (BPI), described in U.S. Patent Nos. 5,627,153, 5,858,974, 5,652,332, 5,763,567 and 5,733,872, the disclosures of all of which are incorporated herein by reference.
  • antibiotics are natural chemical substances of relatively low molecular weight produced by various species of microorganisms, such as bacteria (including Bacillus species), actinomycetes (including Streptomyces) and fungi, that inhibit growth of or destroy other microorganisms.
  • antibiotics include the ⁇ -lactams, including the penicillins, cephalosporins and monobactams; (2) the aminoglycosides, e.g., gentamicin, tobramycin, netilmycin, and amikacin; (3) the tetracyclines; (4) the sulfonamides and trimethoprim; (5) the fluoroquinolones, e.g., ciprofloxacin, norfloxacin, and ofloxacin; (6) vancomycin; (7) the macrolides, which include for example, erythromycin, azithromycin, and clarithromycin; and (8) other antibiotics, e.g., the polymyxins, chloramphenicol and the linco
  • Antibiotics accomplish their anti-bacterial effect through several mechanisms of action which can be generally grouped as follows: (1) agents acting on the bacterial cell wall such as bacitracin, the cephalosporins, cycloserine, fosfomycin, the penicillins, ristocetin, and vancomycin; (2) agents affecting the cell membrane or exerting a detergent effect, such as colistin, novobiocin and polymyxins; (3) agents affecting cellular mechanisms of replication, information transfer, and protein synthesis by their effects on ribosomes, e.g., the aminoglycosides, the tetracyclines, chloramphenicol, clindamycin, cycloheximide, fucidin, lincomycin, puromycin, rifampicin, other streptomycins, and the macrolide antibiotics such as erythromycin and oleandomycin; (4) agents affecting nucleic acid metabolism, e.g., the fluoroquinolones, act
  • BPI protein products are also described to have antibacterial activities in U.S. Patent Nos. 5,198,541 and 5,523,288 and International Publication No. WO 95/08344 (PCT/US94/11255), all of which are incorporated by reference herein, disclosing activity against gram-negative bacteria, and U.S. Patent Nos. 5,578,572 and
  • BPI protein products have been shown to have additional antimicrobial activities.
  • U.S. Patent No. 5,646,114 and International Publication No. WO 96/01647 (PCT/US95/08624), all of which are incorporated by reference herein, disclose activity of BPI protein products against protozoa.
  • Concurrent administration of the XMP.445 peptide for adjunctive therapy with other antimicrobial agents (particularly antifiingal agents) is expected to improve the therapeutic effectiveness of the antimicrobial agents. This may occur through reducing the concentration of antimicrobial agent required to eradicate or inhibit target cell growth, e.g., replication.
  • XMP.445 peptide and another antifiingal agent may produce a more rapid or complete fungicidal or fungistatic effect than could be achieved with either agent alone.
  • Administration of XMP.445 peptide may reverse the resistance of fungi to antifiingal agents or may convert a fungistatic agent into a fungicidal agent. Similar results may be observed upon concurrent administration of XMP.445 with other antimicrobial agents.
  • Therapeutic effectiveness in vivo is based on a successful clinical outcome, and does not require that the antimicrobial agent or agents kill 100% of the organisms involved in the infection. Success depends on achieving a level of antimicrobial activity at the site of infection that is sufficient to inhibit growth or replication of the pathogenic organism in a manner that tips the balance in favor of the host. When host defenses are maximally effective, the antimicrobial effect required may be minimal. Reducing organism load by even one log (a factor of 10) may permit the host's own defenses to control the infection. In addition, augmenting an early microbicidal/microbistatic effect can be more important than a long-term effect. These early events are a significant and critical part of therapeutic success, because they allow time for host defense mechanisms to activate.
  • the invention provides a method of killing or inhibiting growth of pathogenic organisms (particularly fungi) comprising contacting the organism with
  • XMP.445 optionally in conjunction with other antimicrobial agents.
  • This method can be practiced in vivo or in a variety of in vitro uses such as to decontaminate fluids and surfaces or to sterilize surgical and other medical equipment and implantable devices, including prostheses and intrauterine devices. These methods can also be used for in situ sterilization of indwelling invasive devices such as intravenous lines and catheters, which are often foci of infection.
  • a further aspect of the invention involves use of XMP.445 for the manufacture of a medicament for treatment of microbial infection (e.g., fungal or bacterial infection) or a medicament for concurrent administration with another agent for treatment of microbial infection.
  • the medicament may optionally comprise a pharmaceutically acceptable diluent, adjuvant or carrier and also may include, in addition to XMP.445, other chemotherapeutic agents.
  • Example 1 addresses preparation and purification of XMP.445.
  • Example 2 addresses in vitro antifiingal activity testing of XMP.445.
  • Example 3 addresses in vivo antifiingal activity testing of XMP.445.
  • Example 4 addresses testing of XMP.445 for oral availability.
  • Example 5 addresses testing of other properties of XMP.445, including serum stability and activity on cells treated with a membrane potential indicator dye that localizes to mitochondria.
  • XMP.445 was tested for in vitro antifungal activity against Candida albicans, Candida tropicalis, Aspergillus fumigatus, Cryptococcus neoformans, Fusarium solani, Fusarium oxysporum and Scytalidium hyalinum in a broth assay generally according to Example 2 of U.S. Patent No. 5,858,974.
  • XMP.445 was also tested for in vitro antifungal activity in radial diffusion assays against C. albicans SLU-1 generally according to Examples 2 and 3 of U.S. Patent No. 5,858,974.
  • XMP.391 amino acid residues 150-161 of BPI; SEQ ID NO:4
  • XMP.342 amino acid residues 153-157 of BPI with an additional two D- lysines at the N-terminus and an additional two D-lysines at the C-terminus; SEQ ID NO:5) are described in U.S. Patent No. 5,858,974. Additional testing of XMP.445 against various species of Fusarium using the National Committee for Clinical Laboratory Standards macrobroth dilution method, M-27A, showed that XMP.445 exhibited potent activity against all tested species.
  • the minimal fungal growth inhibitory concentrations (MICs) of XMP.445 ranged from 2 to 8 ⁇ g/mL for F. solani, 4 to 32 ⁇ g/mL for F. oxysporium, 2 to 4 ⁇ g/mL for F. moniliforme, 2 to A ⁇ g/mL for F. dimerum and about 4 ⁇ g/mL for F. chlamydosporium.
  • XMP.445 was tested for in vivo antifungal activity in mice with systemic C. albicans infection, as measured by effect on mortality, generally according to Example
  • XMP.445 was also tested for in vivo antifungal activity in cyclosporin A- immunosuppressed mice with systemic C. albicans infection generally according to
  • the cyclosporin A injections were administered daily for 8 days (day -1 to day 7) and XMP.445 was administered at 10 mg/kg once daily for 14 days (day 0 to day 14) via intraperitoneal injection.
  • a reduction in mortality was observed, although the results did not reach statistical significance.
  • XMP.445 Additional testing of XMP.445 in mice infected with an Aspergillus inoculum equivalent to approximately LD 80 over 28 days (about 2 x 10 6 spores in 0.25 ml) showed that administration of XMP.445 (7 doses q.o.d. starting at day 0) provided a trend towards survival benefit, although the results did not reach statistical significance.
  • XMP.445 was also tested in mice infected with Fusarium solani (clinical isolate #99-6, for which the MFC of XMP.445 was previously determined to be approximately 2 to 4 ⁇ g/mL at 24 to 48 hours). Groups of 10 mice were given 150 mg/kg
  • Increasing doses of various BPI-derived peptides were also administered to healthy mice via intravenous injection into the tail vein to determine the maximum tolerated dose of peptide that could be administered without causing observable symptoms such as alterations in respiratory rate and loss of righting reflex.
  • doses of XMP.342 higher than 5 mg/kg were not well tolerated
  • doses of XMP.391 higher than 10 mg/kg were not well tolerated
  • doses of XMP.445 higher than 5 mg/kg were not well tolerated.
  • XMP.445 exhibited the broadest range of therapeutic doses without adverse effects.
  • the minimum effective dose (MED) for XMP.342 was 5 mg/kg (the same as the MTD); the MED for XMP.391 was 5 mg/kg (about half the MTD); the MED for XMP.445 was 0.5 mg/kg (about one-tenth the MTD).
  • the cells were incubated with peptide on the apical side for 2.5 hours in MDCK screening or 4 hours for CACO-2 screening.
  • the transepithelial transport of the peptide was measured by quantitative HPLC analysis of the incubation media on the basolateral side of the cells. Radiolabelled mannitol and cortisone were used as positive controls.
  • XMP.445 was further tested for activity upon oral administration (oral activity) in a 28-day comparative survival efficacy study in mice systemically infected with Candida albicans. Specifically, male DBA/2 mice (Charles River Laboratories) six weeks of age were dosed with 7.9 x 10 4 Candida albicans, SLU-1 in 100 ⁇ intravenously via the tail vein in a single dosage on day 0. Treatment began immediately thereafter with 400 ⁇ l oral gavage of either 0.5% dextrose, or XMP.445 in 0.5% dextrose at levels of either
  • XMP.445 was administered intravenously at 0.5 mg/kg as a positive control every other day for a total of eight times. Twice-day monitoring (once daily on weekends and holidays) for mortality was performed. The animals treated with XMP.445 showed improvements in mortality compared with the dextrose-treated controls, and the animals treated with XMP.445 at 10 mg/kg showed significant improvement (p-value of 0.025). The results of this study show that XMP.445 has oral antifungal activity.
  • XMP.445 was also tested for in vivo oral antifungal activity in cyclosporin A-immunosuppressed mice with systemic C. albicans infection generally according to Example 4 of U.S. Patent No. 5,858,974.
  • the cyclosporin A injections were administered daily for 8 days (day -1 to day 7) and XMP.445 was administered at 10 mg/kg once daily for 14 days (day 0 to day 14) via oral gavage. A reduction in mortality was observed, although the results did not reach statistical significance.
  • XMP.445 was also tested for serum stability using a bioassay generally according to Example 5 of U.S. Serial No. 08/621,259, wherein the peptide is incubated with serum for varying amounts of time and the resulting serum-treated product is tested for antifungal activity against C. albicans SLU-1 in a radial diffusion assay.
  • XMP.445 was further tested for its effect on fiingal cells treated with a membrane potential indicator dye that localizes to mitochondria, as described in co-owned U.S. Provisional Application Serial Nos. 60/101,778 filed September 25, 1998, 60/109,905 filed November 25, 1998, and 60/143,485 filed July 12, 1999, and in co-owned concurrently filed U.S. Application Serial No. [Attorney Docket No. 27129/36271], all of which are incorporated by reference herein.

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Abstract

La présente invention concerne généralement un nouveau peptide, le XMP.445, issu de ou fondé sur le domaine III (acides aminés 142 à 169) d'une protéine bactéricide augmentant la perméabilité (BPI), et des utilisations dudit peptide à des fins thérapeutiques.
PCT/US1999/022277 1998-09-25 1999-09-24 Peptide antifongique et antibacterien WO2000018798A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030975A2 (fr) * 2000-10-11 2002-04-18 Xoma Technology, Ltd. Composé fongicide
US10450348B2 (en) 2013-11-06 2019-10-22 Norwegian University Of Science And Technology Antimicrobial agents and their use in therapy
US10517923B2 (en) 2013-11-06 2019-12-31 Norwegian University Of Science And Technology Immunosuppressive agents and their use in therapy
CN113999296A (zh) * 2021-11-04 2022-02-01 厦门大学 一种拟穴青蟹新型抗菌多肽Spgillcin177-189及其应用
WO2022268115A1 (fr) * 2021-06-25 2022-12-29 厦门大学 Polypeptide antibactérien spampcin 56-86 de scylla paramamosain et son application

Citations (4)

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WO2002030975A3 (fr) * 2000-10-11 2003-04-24 Xoma Technology Ltd Composé fongicide
US10450348B2 (en) 2013-11-06 2019-10-22 Norwegian University Of Science And Technology Antimicrobial agents and their use in therapy
US10517923B2 (en) 2013-11-06 2019-12-31 Norwegian University Of Science And Technology Immunosuppressive agents and their use in therapy
US11246907B2 (en) 2013-11-06 2022-02-15 Norwegian University Of Science And Technology Immunosuppressive agents and their use in therapy
US11337427B2 (en) 2013-11-06 2022-05-24 Norwegian University Of Science And Technology Antimicrobial agents and their use in therapy
WO2022268115A1 (fr) * 2021-06-25 2022-12-29 厦门大学 Polypeptide antibactérien spampcin 56-86 de scylla paramamosain et son application
CN113999296A (zh) * 2021-11-04 2022-02-01 厦门大学 一种拟穴青蟹新型抗菌多肽Spgillcin177-189及其应用
CN113999296B (zh) * 2021-11-04 2022-11-01 厦门大学 一种拟穴青蟹新型抗菌多肽Spgillcin177-189及其应用

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