| Recombinant sp-a for the treatment or prevention of pulmonary infection and inflammation -> Monitor Keywords |
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Recombinant sp-a for the treatment or prevention of pulmonary infection and inflammationRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain StructureRecombinant sp-a for the treatment or prevention of pulmonary infection and inflammation description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060194732, Recombinant sp-a for the treatment or prevention of pulmonary infection and inflammation. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to the novel use of recombinant surfactant protein A for the production of a medicament for the treatment of pulmonary infection and inflammation. PRIOR ART [0002] Pulmonary surfactant plays an important role in maintaining the structural integrity of the alveoli by reducing surface tension. The surfactant consists mostly of a complex mixture of phospholipids and genetically distinct proteins referred to as surfactant protein A, B, C and D (also designated as SP-A, SP-B, SP-C and SP-D). It is synthesized by alveolar type II pneumocytes and secreted as tightly packed lamellar bodies into the alveoli (King, R. J.: Pulmonary Surfactant, J. Appl. Physiol. 1982, 51, 1-8). [0003] SP-A is hypothesized to play a role in protecting the lung from bacterial, viral, and fungal infections (Thiel, S., and Reid, K.: Structures and functions associated with the group of mammalian lectins containing collagen-like sequences, FEBS Lett. 1989, 250, 78). In addition, in vitro, it has been shown that SP-A binds to various micro-organisms, acts as opsonin, enhances killing of micro-organisms by macrophages, down regulates pro-inflammatory cytokines such as TNF-.alpha. induced by LPS or microbial pathogens (reviewed in: Molecular Basis of Disease, Pulmonary surfactant. Ed: L. M. G. van Golde, Biochimica et Biophysica Acta, 1998,1408, 77-364). [0004] Recently, it was shown that mice lacking SP-A are susceptible to group B streptococcal infection (LeVine A. M. et al.: Surfactant protein A-deficient mice are susceptible to group B streptococcal infection; The Journal of Immunology, 1997, 4336-4340) and that exogenous proteinosis SP-A enhanced bacterial clearance in SP-A deficient mice (LeVine A. M. et al.: Surfactant protein-A (SP-A) binds group B streptococcus (GBS), enhancing phagocytosis and clearance from lungs of SP-A deficient mice; Am J. Respir. Crit. Care Med. 1998, Vol. 157, A 865). In addition, it was shown that baboons with bronchopulmonary dysplasia (BPD) and superimposed infection have decreased levels of SP-A present in the lungs (King, R. J., et al.: Surfactant protein-A deficiency in a primate model of pulmonary dysplasia, Am. J. Respir. Crit. Care Med. 1995, 151(6), 1989-97 and Coalson, J. J.: Pathophysiologic, morphometric, and biochemical studies of the premature baboon with bronchopulmonary dysplasia, Am. Rev. Respir. Dis. 1992, 145, 872-81). Furthermore, it was shown that SP-A is decreased in a number of diseases such as pneumonia, asthma, bronchiolitis, lung transplantations, cystic fibrosis, ARDS, smokers etc. as reviewed in M. Griese, Pulmonary surfactant in health and human lung diseases: state of the art. Eur. Respir. J. 1999, 13, 1455-1476. It was also shown, that SP-A inhibits allergen induced histamine release as well as the proliferation of lymphocytes in cells isolated from allergen exposed asthmatics. (Wang, J. Y. et al., Inhibitory effect of pulmonary surfactant proteins A and D on allergen-induced lymphocyte proliferation and histamine release in children with asthma. Am. J. Respir. Crit. Care Med., 1998, 158, 510-518; Mandan, T. et al., Lung surfactants proteins A and D can inhibit specific IgE binding to the allergens of Aspergillus fumigatus and block allergen-induced histamine release from human basophils. Clin. Exp. Immunol., 1997, 110, 241-249). SUMMARY OF THE INVENTION [0005] The subject invention has several distinct aspects. One aspect is the use of a component which is at least substantially the same as recombinant surfactant protein A (rSP-A) for treating or preventing a pulmonary infection or inflammation. Another aspect is a medicament composition for treating or preventing a pulmonary infection and inflammation, and which comprises an active component which is at least substantially the same as recombinant surfactant protein A. A further aspect is a method of compounding such a medicament composition. A still further aspect comprises the concurrent use of surfactant protein D (SP-D) with an active component which is at least substantially the same as recombinant surfactant protein A in treating or preventing a pulmonary infection and inflammation, in compounding a medicament composition and in the resulting medicament composition itself. An additional aspect of the invention is an article of manufacture, comprising packaging material and rSP-A or a compound which is substantially the same as rSP-A (in a container) within the packaging material, and the packaging material including a label or instructions which indicate usefulness for the treatment or prevention of inflammation or microbial infection. BRIEF DESCRIPTION OF THE DRAWINGS [0006] FIG. 1 graphically illustrates that the clearance of GBS in the SP-A (-/-) mice was significantly enhanced at 6 and 24 hours when GBS was co-administered with 150 .mu.g rSP-A. [0007] FIG. 2 graphically illustrates that GBS clearance by SP-A (-/-) mice is dose dependent and is increased by increased amount of rSP-A. [0008] FIG. 3 graphically illustrates the clearance of GBS in wild-type mice is significantly enhanced at 6 and 24 hours when GBS is co-administered with 150 .mu.g rSP-A. [0009] FIG. 4 graphically illustrates that wild-type animals infected with GBS and treated 6 hours after infection with intratracheal rSP-A have increased clearance of GBS at 24 hours. [0010] FIG. 5 graphically illustrates that exogenous rSP-A reduces TNF-.alpha. content in lung homogenates from SP-A (-/-) mice challenged with GBS close to the level observed in SP-A (+/+) mice. DETAILS [0011] Surprisingly it has now been found that recombinant surfactant-associated protein A (rSP-A) can be used in the treatment or prevention of pulmonary infection and inflammation and is equivalent or superior to the use of surfactant-associated protein A (SP-A) obtained from natural sources, for example that isolated from lavage fluid from healthy individuals or proteinosis patients. This must be regarded as particularly surprising as SP-A isolated from human lung lavage consists of a homogenous population of a flower bouquet like hexameric structure, each unit of which consists of three SP-A polypeptide chains (.alpha.1), analogous to that described for the complement factor C1q. The fully assembled hexameric structure is thought to be essential for a functional molecule with respect to stimulating anti-microbial defense mechanisms or anti-inflammatory activity. In contrast to the naturally derived SP-A, surfactant-associated protein A produced by recombinant techniques consists of a variety of different oligomeric structures ranging from one single polypeptide chain (.alpha.1) to the fully assembled octadecameric form (.gamma.6) (Voss, T., et al.: Macromolecular organization of natural and recombinant lung surfactant protein SP 28-36; J. Mol. Biol. 1988, 201, 219-227; Voss et al.: Structural comparison of recombinant pulmonary surfactant protein SP-A derived from two human coding sequences: Implications for the chain composition of natural human SP-A, Am. J. Respir. Cell Mol. Biol., 1991, 4, 88-94). [0012] In addition it was shown, that natural derived SP-A is glycosylated. However, although recombinant produced SP-A, depending on the system used for expression (mammalian, insect, or yeast cells), shows different glycosylation patterns, it shows anti-microbial or anti-inflammatory effects superior or equivalent to the natural SP-A. [0013] As used herein microbial refers to bacterial, viral or fungal. [0014] As used herein recombinant surfactant-associated protein A (hereinafter also referred to as rSP-A) refers to vertebrate, preferably mammalian, surfactant-associated protein A produced by recombinant techniques. Amino acid sequences and DNA sequences coding for mammalian surfactant-associated protein A are, for example, described in WO86/03408, WO88/05820 and U.S. Pat. No. 4,882,422. Recombinant surfactant-associated protein A further refers to derivatives of vertebrate, preferably mammalian, surfactant-associated protein A produced by recombinant techniques which differ from natural mammalian or other vertebrate surfactant-associated protein A by addition, deletion or substitution of amino acids as long as the proteins retain microbial clearance activity or anti-inflammatory activity. Such activity of recombinant surfactant-associated protein A can, for example, be determined in an assay according to the one hereinafter described for group B streptococcus bacteria. In a preferred embodiment rSP-A refers to human surfactant-associated protein A produced by recombinant methods and having an amino acid sequence encoded by a DNA sequence contained in cDNA clones, pHS10-5, pHS10-4, PSAP-1A, PSAP-6A and a genomic clone pHS-15 or an allelic variation thereof. Two genes (designated as A1 and A2) coding for SP-A have been Identified in the human genome (White, R. T. et al.: Nature 1985, 317, 361-363; Katyal, S. L. et al.: Am. J. Respir. Cell Mol. Biol., 1992, 6:446-452). The genomic clone pHS-15 coding for human SP-A has been described in WO86/03408, and clones containing cDNA sequences coding for SP-A have been described in WO88/05820 for pHS10-5 and pHS10-4, and by Floros et al., The Journal of Biological Chemistry, 1986, 261, 9029-33 and U.S. Pat. No. 4,882,422 for PSAP-1A and PSAP-6A). Recombinant SP-A may be obtained according to procedures known in the art. Methods for cloning and production of rSP-A are for example described in WO86/03408, WO88/05820, U.S. Pat. No. 4,659,805, U.S. Pat. No. 4,912,038, Voss, T., et al.: Macromolecular organization of natural and recombinant lung surfactant protein SP 28-36; J. Mol. Biol. 1988, 201, 219-227, and Voss et al.: Structural comparison of recombinant pulmonary surfactant protein SP-A derived from two human coding sequences: Implications for the chain composition of natural human SP-A, Am. J. Respir. Cell Mol. Biol., 1991, 4 88-94). [0015] In the text and drawings n refers to the number of animals (mice), and wt refers to "wild-type". As used in the claims, "substantially the same as" includes a) derivatives of surfactant-associated protein A produced by recombinant techniques, but which differ from natural surfactant-associated protein A by addition, deletion or substitution of one or more amino acids, b) SP-A modifications which differ in type and/or degree of glycosylation, and c) recombinant fusion proteins consisting of the complete or portions of the SP-A fused with suitable proteins or parts thereof having anti-infective or anti-inflammatory activities, as long as the surfactant-associated proteins A retain microbial clearance activity or anti-inflammatory activity, as determined by assay. [0016] Examples which may be mentioned in connection with deleted, truncated or mutated forms of rSP-A are the SP-A-glob variant in which the amino acids of the collagenous domain were deleted (aa 17-80) or other forms as described in Spissinger et al., Assembly of the surfactant protein SP-A. Eur. J. Biochem., 1991, 199, 65-71. [0017] Exemplary proteins having anti-infective or anti-inflammatory activities which may be mentioned in connection with recombinant fusion proteins are proteins such as defensins, lysozymes, cytokines, chemokines and immunoglobulins. These proteins can be fused to either the C- or N-terminal end of SP-A. [0018] In one embodiment of the invention recombinant SP-A obtainable by expression of a DNA sequence coding for SP-A in a suitable eucaryotic expression system is used for the manufacture of a medicament for the prevention or treatment of pulmonary infection and inflammation. Suitable expression systems are, for example, CHO-cells using suitable expression vectors. Suitable expression vectors are, for example: pMT(E) Apo containing the SV40 enhancer and the inducible human metallothionin promoter (Fritz et al., Proc. Natl, Acad. Sci. USA, 83:4114-4118), pRc/CMV for constitutive expression of the gene of interest (Invitrogen, Leek, Netherlands) or any other expression vector useful for mammalian cells containing homologous intron sequences (i.e., authentic genomic sequences from the gene of interest) or heterologous intron sequences. In this case it is further preferred to use a partial or complete genomic sequence coding for SP-A, for example a genomic sequence as described in WO86/03408 for the A1 gene yielding a higher expression rate and subsequently to higher order structures of SP-A (Voss et al.: Structural comparison of recombinant pulmonary surfactant protein SP-A derived from two human coding sequences: Implications for the chain composition of natural human SP-A, Am. J. Respir. Cell Mol. Biol., 1991, 4:88-94). This approach would also apply for the A2 gene described by Katyal, S. L. et al. (Am. J. Respir. Cell Mol. Biol., 1992, 6:446-452). Preferentially the expression of the genomic sequence coding for SP-A in a suitable expression system is carried out as described by Voss et. al. (Am. J. Respir. Cell Mol. Biol. 1991, 4, 88-94). [0019] In addition, to express the cDNA sequences coding for SP-A (A1/A2) it is preferred to use either insect cells using the Baculovirus expression system (McCormack, F. et al., J. Biol. Chem., 1994, 269:5833-5841) or yeast, such as Pichia pastoris, in both cases with or without co-expression of the human prolyl 4-hydroxylase stabilizing the collagen helices by hydroxylating proline residues in the collagenous domain as demonstrated for the expression of collagen (Lamberg, Arja et al., J. Biol. Chem., 1996, 271:11988-11995; Vuorela, A. et al., EMBO J., 1997,16:6702-6712). For example rSP-A can be produced by cloning of the respective cDNAs into the EcoRI site of the Baculovirus expression vector pVL1392, subsequent generation of recombinant viruses and expression in SF21 cells using standard procedures. rSP-A may also be produced in yeast (for example Pichia pastoris) after cloning of the respective cDNAs into yeast expression vectors such as pPICZ A (Invitrogen, Leek, Netherlands) for the expression in Pichia pastoris. Continue reading about Recombinant sp-a for the treatment or prevention of pulmonary infection and inflammation... Full patent description for Recombinant sp-a for the treatment or prevention of pulmonary infection and inflammation Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Recombinant sp-a for the treatment or prevention of pulmonary infection and inflammation patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. 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