US20030004309A1 - Immunological enhancement agent comprising N-terminal peptide of p43 as an effective component - Google Patents

Immunological enhancement agent comprising N-terminal peptide of p43 as an effective component Download PDF

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US20030004309A1
US20030004309A1 US09/930,169 US93016901A US2003004309A1 US 20030004309 A1 US20030004309 A1 US 20030004309A1 US 93016901 A US93016901 A US 93016901A US 2003004309 A1 US2003004309 A1 US 2003004309A1
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protein
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Sunghoon Kim
Young-Gyu Ko
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Imagene Co Ltd
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Imagene Co Ltd
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Assigned to IMAGENE CO., LTD. reassignment IMAGENE CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KIM, SUNGHOON, KO, YOUNG-GYU
Publication of US20030004309A1 publication Critical patent/US20030004309A1/en
Priority to US10/823,730 priority Critical patent/US7037505B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • 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 to an immunological enhancement agent, more particularly, to an immunological enhancement agent comprising specific peptides having immunological activity as an effective component.
  • EMAP II Endothelial monocyte-activating polypeptide II
  • the EMAP II is the C-terminal domain of the p43 protein—the precursor of the EMAP II, consisting of 312 amino acids—and it is cleaved to form by caspase-7, in which aspartic acid—the 146th amino acid of p43 protein—is activated in apoptotic cells (Quevillion, S. et al., J. Biol. Chem., 272:32573-32579, 1997; Behrensdorf, M. A. et al., FEBS Lett., 466:143-147, 2000).
  • EMAP II The structure and maturation of the EMAP II is similar to that of an IL-1 ⁇ , a cytokine involved in a proinflammatory response, and 14.5 kDa of the IL-1 ⁇ is cleaved to form from 33 kDa of inactive pre-IL-1 ⁇ by ICE (caspase-1).
  • An EMAP II is the mediator of proinflammatory response that induces the expression of tissue factor, tumor necrosis factor (hereinafter, referred to as “TNF”) and interleukin-8 (hereinafter, referred to as “IL-8”) in mononuclear phagocyte and polymorphonuclear leucocytes.
  • TNF tumor necrosis factor
  • IL-8 interleukin-8
  • EMAP II is a chemotaxis material leading macrophage to dead cells. It is known that the EMAP II acts as a cytokine, and the 15 amino acids of the N-terminal domain of an EMAP II play a vital role in the reaction (Quevillon, S. et al., J. Biol. Chem., 272:32573-32579, 1997; Kao, J. et al., J. Biol. Chem., 269:9774-7982, 1994; Kao, J. et al., J. Biol. Chem., 267:20239-20247, 1992; Kao, J. et al., J. Biol.
  • the p43 protein is expressed extensively.
  • the expression level of p43 protein varies temporally and spatially, especially in a developing mouse. For example, it was shown that the expression of a p43 in the lung of mouse from 8 days to 16 days after its birth was increased dramatically.
  • the p43 is highly expressed in the microglial cells in the lesions of autoimmune disease such as encephalomyelitis, neuritis and uveitis.
  • the high expression level of the p43 in specific developmental stage and tissues suggests that the p43 could have unexpected functions in angiogenesis, inflammation, and apoptosis (fas, M. P. R., and Marray, J. C., Int. J. Biochem. Cell.
  • the present inventors compared the secretion pattern of a p43 with that of an EMAP II in normal cells and apoptotic cells, and reported that the cytokine acting in physiological condition was the p43 and not the EMAP II. Since the EMAP II is secreted during the late stage of apoptosis in which cells are completely destroyed in normal cells, it is not active in the early stage of apoptosis; whereas, the p43 is constitutively secreted from various cells irrespectively of apoptosis (Ko YG et al., A cofactor of tRNA synthetase, p43, is secreted to up-regulate proinflammatory genes, J. Biol. Chem. 2001, Apl 5, 276).
  • the present invention provides an immunological enhancement agent that comprises a peptide having an amino acid sequence represented by SEQ ID NO:1 to SEQ ID NO:3 as an effective component.
  • the p43(1-147), the p43(1-108) and the p43(91-256), which comprise the N-terminal domain of the p43 protein can act as a cytokine to increase the amount of the TNF and the IL-8. As a result, they can improve an immune response and be used as an effective immunological enhancement agent.
  • FIG. 1 shows the relative location and the size of the deletion-mutants of a p43 prepared in the present invention compared to a normal p43.
  • FIG. 2 shows the result of the SDS-PAGE analysis of the deletion-mutants of the p43 prepared in the present invention and the p43 protein after purification.
  • FIG. 3 illustrates the amount of the TNF produced after incubation of human monocyte THP-1 cells to which the purified p43 protein and its deletion-mutants are added respectively.
  • FIG. 4 illustrates the amount of the IL-8 produced after incubation of human monocyte THP-1 cells to which the purified p43 protein and its deletion-mutants are added respectively.
  • the deletion-mutants of the p43 protein were constructed. Then they were purified and added to cultivated mammalian cells. Next, the degree of inducing the production of cytokine was measured. Finally, the peptides showing a high level of cytokine induction in cultivated mammalian cells could be isolated from various deletion-mutants of the p43 protein.
  • recombinant vectors were respectively prepared according to known technique (Park, S. G. et al., J. Biol. Chem., 274:166673-16676, 1999).
  • the recombinant vectors include the following genes respectively encoding: the p43(1-312), which is the p43; the p43(148-312), which is the C-terminal domain of the p43 or the EMAPII; the p43(1-147), the p43(1-108), and the p43(91-256) which include N-terminal part of the p43.
  • the vectors for cloning the above genes are not limited to specific vectors, but pET28a is preferable.
  • the p43 protein and its deletion mutants can be expressed by transforming host cell with the prepared vectors including gene of the p43 or its deletion mutants.
  • the host cell for transformation is not limited specifically, but E.coli is preferable.
  • the cytokine activity of the p43 and its deletion-mutants protein was investigated.
  • the expressed proteins were added to a mammalian cell cultured in serum-free media, and the amount of inducing production of other cytokines was measured.
  • the mammalian cell is not specifically limited if only it is a growth factor dependent cell, however, a human monocyte THP-1 cell is more preferable.
  • Whether or not the above proteins have immunological activity was investigated by measuring the amount of cytokine produced that can be induced by the p43 or its deletion-mutant proteins. More particularly, among cytokines the amount of the TNF and the IL-8 produced was measured in the present invention.
  • ELISA Enzyme-Linked Immuno Sandwich Assay
  • the p43(1-147), the p43(1-108) and the p43(91-256), the peptides represented by SEQ ID NO:1 to SEQ ID NO:3 according to the present invention showed cytokine activity and induced the production of the TNF and the IL-8.
  • the produced amount of the TNF and the IL-8 induced by the above peptides was higher by 2-3 times more than that by EMAP II.
  • the produced amount of the TNF and the IL-8 induced by the peptide represented by SEQ ID NO: 1 was higher by 1.1 times more than by the p43 and higher by 2.5-3 times more than by EMAP II.
  • the immonological enhancement agent according to the present invention that comprises the N-terminal part of the p43 as an effective component is not limited to a specific form, if only it is a feasible form for being administered to human and animals. Also, it can be a form supported with carrier.
  • the carrier at least one of a solid, a liquefied diluent, a filling agent, and other assistant can be used with the ratio of 0.1 ⁇ 99.5%.
  • the immunological enhancement agent can be administered orally or non-orally.
  • the non-oral administration can be tissue partial-, hypodermal-, intramuscular-, arterial-, intravenous-, and rectal administration.
  • the preferable administration form can be prepared in conventional techniques.
  • Oral administration can be done by using a solid or liquid form; for example, bulk powders, powders, granules, tablets, capsules, syrups, suspensions, etc. If necessary, the unit administration form for oral administration can be microcapsulated.
  • the extension of the activity period and the sustained release of a formulation can be obtained by coating the formulation or inserting its active components to polymer or wax.
  • the administration amount of the immunological enhancement agent can be determined preferably by taking into consideration for the age of patient, the body weight, a method of administration, any disease and its state, and so on.
  • the recombinant vector including the p43(1-147) gene, was prepared by known method in the art (Park, S. G. et al., J. Biol. Chem., 274:16673-16676, 1999). Plasmid pM388 provided from Dr. Kiyotaka Shiba in Japan Cancer Institute was restricted with NdeI and XhoI to obtain the p43 gene, and it was used as a template. The PCR was performed using the forward and reverse primer represented by SEQ ID NO:4 and SEQ ID NO:5 respectively, under the condition as follows; 1 min at 95° C., 1 min at 58° C., and 1 min at 72° C. The resulting PCR product was restricted with EcoRI and Sall and inserted into pET28a (Novagen, Madison, USA) to prepare the recombinant vector.
  • E.coli BL21(DE3) was transformed with the above recombinant vector including the p43(1-147) gene.
  • the transformed BL21 was cultured in 100 ml of LB medium (Luria Broth; Ig NaCl, 1 g Bacto-tryptone, 0.5 g yeast extracts) and the p43(1-147) gene was expressed as a His-tag fusion protein form.
  • the expressed p43(1-147) protein was purified by using nickel affinity chromatography and mono Q or S ion-exchange chromatography according to known method in the art (Park, S. G. et al., J. Biol. Chem., 274:16673-16676, 1999).
  • the purified protein was dialyzed with the pyrogen-free buffer solution (10 mM potassium phosphate (pH 6.0), 100 mM NaCl) overnight. After dialysis, the protein was loaded to a polymyxin resin (Bio-Rad) that was equilibrated with the same buffer, incubated for 20 minutes and eluted. The concentration of the remaining lipopolysaccharide was measured using the Limulus Amebocyte lysate QCL-1000 kit (Bio Whittacker). As a result, the concentration of the lipopolysaccharide was below 20 pg/ml—not able to induce inflammatory response. The purified protein was then subjected to SDS-PAGE. As shown in FIG. 2, it was confirmed that the p43(1-147) protein having the molecular weight of 21 kDa was isolated purely.
  • the recombinant vector, including the p43(1-108) gene was prepared according to the same method described in the Example 1.
  • the recombinant vector pET28a (Novagen) containing the p43(1-312) gene was restricted with AspI and SalI.
  • the restricted recombinant vector was treated with the klenow fragment to fill up the DNA ends and re-ligated.
  • the recombinant vector, including the p43(1-108) gene was prepared by treating ligase and making the vector self-ligation.
  • BL21 was transformed with the recombinant vector, including the p43(1-108) gene, according to the same method described in the Example 1.
  • the expressed p43(1-108) protein was purified and analyzed by SDS-PAGE.
  • the recombinant vector, including the p43(91-256) gene was prepared according to the same method described in the Example 1, except that the PCR was performed using the forward and reverse primer represented by SEQ ID NO:6 and SEQ ID NO:7 respectively, under the condition as follows; 30 sec at 95° C., 30 sec at 50° C., and 40 sec at 72%C.
  • BL21 was transformed with the recombinant vector, including the p43(91-256) gene, according to the same method described in the Example 1.
  • the expressed p43(91-256) protein was purified and analyzed by SDS-PAGE.
  • the human monocyte THP-1 cells (supplied from the ATCC and cultured selecting the sensitive cells to lipopolysaccharide) were inoculated to the RPMI1640 medium containing 10% fetal bovine serum (FBS) and 50 ⁇ g/ml streptomycin and penicillin, and cultured in 5% CO 2 at 37° C.
  • the cultured cells were washed twice with serum-free RPMI1640, and then 2 ⁇ 10 6 cells/ml were inoculated into 24-well plate containing 0.5 ml of serum-free RPMI1640 medium.
  • the cells were cultured for 2 hours under the same condition, and stimulated for 4 hours by adding 100 nM of the proteins purified in the Example 1-3 respectively.
  • the supernatants were collected, and the concentration of the TNF and the IL-8 was measured using the ELISA kit (PharMingen) according to the manufacturer's instructions.
  • the stimulation experiments were repeated twice. The results of the experiments were shown in FIG. 3 and FIG. 4, respectively.
  • the recombinant vector, including the p43(1-312) gene was prepared according to the same method described in the Example 1, except that the PCR was performed using the forward and reverse primer represented by SEQ ID NO:8 and SEQ ID NO:9 respectively, and the pM338 as a template, and NdeI and XhoI were used as restriction enzymes.
  • BL21 was transformed with the recombinant vector, including the p43(1-312) gene, according to the same method described in the Example 1.
  • the expressed p43(1-312) protein was purified and analyzed by SDS-PAGE.
  • the recombinant vector, including the p43(148-312) gene, encoding EMAP II was prepared according to the same method described in the Example 1, except that the PCR was performed using the forward and reverse primer represented by SEQ ID NO:10 and SEQ ID NO:11 respectively, and pM338 as a template.
  • BL21 was transformed with the recombinant vector, including the p43(148-312) gene, according to the same method described in the Example 1.
  • the expressed p43(148-312) protein was purified and analyzed by SDS-PAGE.
  • the result illustrates that the N-terminal part of the p43 plays a vital role in the cytokine activity. Therefore, the peptides of the present invention comprising the N-terminal domain of the p43 can be used as an immunological enhancement agent showing an excellent cytokine activity.

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US20110124582A1 (en) * 2007-02-01 2011-05-26 Atyr Pharma, Inc. Novel polypeptide having anti-tumor activity
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US8753638B2 (en) 2009-03-16 2014-06-17 Atyr Pharma, Inc. Compositions and methods comprising histidyl-TRNA synthetase splice variants having non-canonical biological activities
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US20040185060A1 (en) * 2001-06-05 2004-09-23 Imagene Co., Ltd. Immunological enhancement agent comprising N-terminal peptide of p43 as an effective component
EP1848395A1 (en) * 2005-02-01 2007-10-31 aTyr Pharma, Inc. Method for stimulation collagen synthesis and/or kgf expression
US20100167997A1 (en) * 2005-02-01 2010-07-01 Atyr Pharma, Inc. Method for stimulation collagen synthesis and/or kgf expression
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