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WO2009096088A1 - Peptide arthritogène - Google Patents

Peptide arthritogène Download PDF

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Publication number
WO2009096088A1
WO2009096088A1 PCT/JP2008/071424 JP2008071424W WO2009096088A1 WO 2009096088 A1 WO2009096088 A1 WO 2009096088A1 JP 2008071424 W JP2008071424 W JP 2008071424W WO 2009096088 A1 WO2009096088 A1 WO 2009096088A1
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Prior art keywords
arthritis
peptide
amino acid
inducing
gpi
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Ceased
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Japanese (ja)
Inventor
Isao Matsumoto
Takayuki Sumida
Keiichi Iwanami
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University of Tsukuba NUC
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University of Tsukuba NUC
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/90—Isomerases (5.)
    • C12N9/92—Glucose isomerase (5.3.1.5; 5.3.1.9; 5.3.1.18)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/10—Animals modified by protein administration, for non-therapeutic purpose
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0325—Animal model for autoimmune diseases

Definitions

  • the present invention relates to an arthritis-inducing peptide. More specifically, an arthritis-inducing peptide capable of easily and stably inducing stable arthritis at any timing by immunizing an animal, an arthritis induction method using the same, an arthritis animal model, and this arthritis animal model
  • the present invention relates to a pharmacological test method using
  • RA Rheumatoid arthritis
  • RA treatment includes medical treatment using anti-rheumatic drugs to delay the progression of joint destruction.
  • symptomatic treatment using non-steroidal anti-inflammatory analgesics (NSAIDs) to control pain is also being carried out.
  • NSAIDs non-steroidal anti-inflammatory analgesics
  • Non-Patent Document 1 As an animal model using a joint-specific antigen, there is a type II collagen-induced arthritis model produced by immunizing animals such as mice and rats with type II collagen which is a component of cartilage (see Non-Patent Document 1). .
  • the type II collagen-induced arthritis model is still used as the most standard arthritis model.
  • arthritis can also be induced by immunization with aggrecan constituting the extracellular matrix of joints.
  • K / BxN mice are known as an autoantibody-inducing animal model (see Non-Patent Document 2). This mouse was discovered by chance by crossing a mouse introduced with the KRN-T cell receptor (TCR) transgene with a NOD (Non obese Diabetic) mouse, which is one of the autoimmune disease models. . K / BxN mice develop chronic progressive arthritis as early as 25-35 days after birth.
  • TCR KRN-T cell receptor
  • NOD Non obese Diabetic
  • the present inventors are able to induce arthritis in normal mice by intraperitoneal administration of K / BxN mouse serum, and by administration of only the immunoglobulin (IgG) fraction in the serum.
  • IgG immunoglobulin
  • this arthritis-inducing antibody is an autoantibody against glucose-6-phosphatase isomerase (GPI) (see Non-Patent Document 3).
  • GPI glucose-6-phosphatase isomerase
  • Patent Document 1 discloses a method for diagnosing arthritis including detection of the presence of autoantibodies to GPI in a sample of patient plasma or serum. This is a disclosure made by the inventors including the present inventor based on the findings reported in Non-Patent Document 3.
  • the document “Claim 13” describes “arthritic animals induced by injection of antibodies against GPI or arthritic K / BxN transgenic mouse mice or fractions thereof”.
  • “Claim 8” “use of GPI-like protein containing GPI-like portion capable of interacting with GPI or autoantibody and inhibiting the autoantibody for the treatment or prevention of arthritis” is described.
  • “Claim 11” includes “a compound that contains or mimics GPI or a GPI part constituting an immunostimulatory epitope for inducing immune tolerance against GPI and preventing the generation of autoantibodies.
  • “Use” is described. These descriptions suggest partial peptides of GPI protein, but these partial peptides are used to treat arthritis and prevent the generation of autoantibodies. It is not used.
  • the specific amino acid sequence of the GPI peptide is not disclosed in this document.
  • joint-specific antigens such as type II collagen and aggrecan as described above
  • the construction of expression vectors, the cultivation of host cells such as Escherichia coli and insect cells, and the extraction and purification of recombinant proteins required a lot of work.
  • the K / BxN mouse which is an autoantibody-inducing animal model, spontaneously develops arthritis, and thus does not require the effort for antigen preparation as described above.
  • the mouse is a single T cell receptor-introduced mouse and that arthritis cannot be induced at the timing necessary to develop arthritis in a relatively short period of 25-30 days after birth.
  • the present invention provides arthritis induction that can easily induce stable arthritis at any timing by immunizing an animal, compared to conventional models using joint-specific antigens or autoantibody-inducing models.
  • the main objective is to provide protogenic peptides.
  • the present invention provides an arthritis-inducing peptide having the amino acid sequence shown below.
  • the arthritis-inducing peptide includes the amino acid sequence described in SEQ ID NO: 1, and more specifically, the amino acid sequence described in SEQ ID NO: 2 or 3.
  • the present invention also provides an arthritis induction method characterized by inducing arthritis in an animal by immunizing the non-human animal with the arthritis-inducing peptide, and an arthritis animal model produced by the arthritis induction method Furthermore, a pharmacological test method for evaluating the pharmacological effect of a test substance on arthritis using the animal model for arthritis is provided.
  • Glucose-6-phosphatase isomerase GPI
  • GPI Glucose-6-phosphatase isomerase
  • the present inventors have now attempted to identify a T cell epitope of the GPI protein for the purpose of obtaining an arthritis-inducing peptide.
  • the following binding epitopes were identified as GPI T cell epitopes, and peptides containing these binding epitopes have strong arthritis-inducing properties. It was found to have
  • the arthritis-inducing peptide containing this binding epitope includes a 9-mer amino acid sequence described in SEQ ID NO: 1, more specifically a 15-mer described in SEQ ID NO: 2 or a 20-mer described in SEQ ID NO: 3. Of the amino acid sequence.
  • the arthritis-inducing peptide according to the present invention only needs to have one or two or more of the above-mentioned binding epitopes in its amino acid sequence, and the peptide length (number of amino acid residues) is also normal.
  • the peptide is not particularly limited as long as the peptide has a length that can be synthesized by a peptide synthesis method.
  • the arthritis-inducing peptide can be synthesized by a conventionally known solid phase synthesis method or liquid phase synthesis method.
  • the currently popular solid phase synthesis method can be carried out using a peptide synthesis resin such as chloromethyl resin, hydroxymethyl resin, benzhydrylamine resin, aminomethyl resin, 4-benzyloxybenzyl alcohol resin. it can.
  • a peptide synthesis resin such as chloromethyl resin, hydroxymethyl resin, benzhydrylamine resin, aminomethyl resin, 4-benzyloxybenzyl alcohol resin.
  • amino acids in which the ⁇ -amino group and the side chain functional group are appropriately protected are condensed on the resin using various condensation methods according to the sequence of the target peptide. After the reaction, the protein is excised from the resin, and at the same time, various protecting groups are removed to obtain the target peptide.
  • arthritis is induced by immunizing non-human animals with these arthritis-inducing peptides.
  • this induction method it is possible to induce arthritis using the shortest peptide of 9mer peptide described in SEQ ID NO: 1 and the longer peptide of 15mer described in SEQ ID NO: 2 or 20mer peptide described in SEQ ID NO: 3 It is.
  • These peptides can be synthesized easily and with high purity by the above synthesis method. Therefore, according to the arthritis induction method according to the present invention, unlike the conventional induction method using a recombinant protein, an antigen is easily prepared, and stable arthritis is induced using the obtained high-purity antigen. Is possible.
  • Immunization with arthritis-inducing peptide is inoculated to animals alone or with an adjuvant.
  • Various adjuvants such as complete Freund's adjuvant and incomplete Freund's adjuvant alum can be used as the adjuvant.
  • Animal inoculation can be performed by intradermal administration, subcutaneous administration, intraperitoneal administration, or the like.
  • an additional adjuvant such as Pertusssis Toxin (pertussis toxin: PT) may be inoculated at the same time as peptide immunization and / or at a predetermined time after immunization.
  • Pertusssis Toxin pertussis toxin: PT
  • arthritis is induced by the arthritis induction method described above.
  • This animal model of arthritis can induce arthritis showing typical clinical and histopathological findings in a short period of 8 days after immunization in mice, for example, by immunization with arthritis-inducing peptide. For this reason, unlike conventional models that spontaneously develop arthritis, it is possible to induce arthritis at any necessary timing.
  • mice mammals other than humans (eg, mice, rats, rabbits, dogs, cats, monkeys, sheep, pigs, cows, horses, etc.) and birds (eg, chickens, etc.) can be used.
  • Arthritis can be preferably induced particularly in mice and rats, but animals other than these are not excluded.
  • the arthritis-inducing peptide according to the present invention is also an example.
  • the arthritis animal model according to the present invention is an animal that expresses I-Aq in particular as MHC class II. This makes it possible to induce arthritis with the highest sensitivity.
  • GPI-induced arthritis is known to be induced in SJL / J mice, and it is naturally possible to induce arthritis in animals expressing MHC class II whose I-As and other anchors are unknown. is there.
  • this animal model for arthritis can be suitably used for a pharmacological test for obtaining an arthritis therapeutic agent capable of preventing, treating or improving arthritis including human RA, for example. Determination of the pharmacological effect of the test substance by administering the candidate substance of the therapeutic agent to the model animal before or after immunization with the arthritis-inducing peptide, and evaluating the presence or absence of the induced arthritis symptoms or the degree of improvement Is possible.
  • this pharmacological test method can induce arthritis in animals at any necessary timing according to the test schedule, and thus can be a highly valuable method.
  • Example 1 Estimation of GPI T cell epitope>
  • the present inventors have found an antibody against glucose-6-phosphatase isomerase (GPI) as an autoantibody having arthritis-inducing activity from serum of K / BxN mice, and can induce arthritis in normal mice by administration of anti-GPI antibody. (See Non-Patent Document 3 above). Furthermore, it has been reported so far that arthritis can be induced in normal mice by immunization with the GPI protein itself, and in particular, it can be significantly induced in DBA / 1 mice (see Non-Patent Document 4 above). Thus, the present inventors have identified a T cell epitope of GPI protein for the purpose of obtaining an arthritis-inducing peptide.
  • GPI glucose-6-phosphatase isomerase
  • MHC class II (hereinafter referred to as "MHC-II") is a non-covalent bond between a 33-35kDa ⁇ chain consisting of about 230 amino acids and a 27-29kDa ⁇ chain consisting of about 230 ⁇ ⁇ amino acids. It is a membrane-bound glycoprotein that binds and is expressed on the plasma membrane surface. The extracellular part of the ⁇ chain and ⁇ chain is divided into two domains each consisting of about 90 amino acids, and is composed of ⁇ 1, ⁇ 2, ⁇ 1 and ⁇ 2 domains.
  • the ⁇ 1 and ⁇ 2 domains that make up the tip of MHC-II (the side far from the plasma membrane) have a groove-like structure in which the ⁇ helix structure forms the side wall and the ⁇ sheet structure forms the bottom surface. Binds to this groove (peptide-containing groove).
  • a peptide consisting of 10 to 30 or more amino acids (mostly around 15) is bound in an expanded form.
  • the amino acid residues on both terminal sides of the peptide are in a state of protruding from the peptide accommodating groove, and only about nine amino acid residues are accommodated in the peptide accommodating groove.
  • the peptide in the peptide accommodation premises rotates in the direction of the side chain every time one amino acid residue is advanced.
  • the side chain of the amino acid residue toward MHC-II on the peptide serves as an anchor, and this is successfully accommodated in 3 to 5 pockets existing in the peptide accommodation structure on the MHC-II side. Containment structure is combined.
  • the side chain of the residue intervening between the anchor amino acids is exposed from the peptide accommodation groove and is recognized by TCR (T-cell receptor).
  • each MHC-II can only bind to a peptide having a specific structure having an anchor amino acid suitable for the peptide accommodation structure and pocket shape of the MHC-II.
  • Bindable peptide structure determined for each MHC-II is called “binding motif”.
  • a binding motif is defined by a combination of “position” and “kind” of anchor amino acids in the amino acid sequence of the peptide. Therefore, by examining the primary structure of the peptide and determining the presence or absence of the binding motif, it can be estimated whether or not the peptide binds to a predetermined MHC-II.
  • the anchor amino acid in I-Aq which is MHC class II expressed in DBA / 1 mice, is the 1st (P1), 4th ( P4) and 7th (P7) is known to be located (“T cell response of I-Aq mice to self type II collagen: meshing of the binding motif of the I-Aq molecule with repetitive sequences results in autoreactivityto multiple epitopes. ”International Immunology, 1997, Vol.9, No.11, p.1687-1699).
  • the numerical value attached to the protein name indicates the amino acid sequence corresponding to the epitope by the amino acid number from the N-terminus in the amino acid sequence of each protein.
  • bold letters indicate amino acids located at P1, P4, and P7 of the binding motif in the epitope.
  • Cited references are shown below.
  • FIG. 1 is a diagram showing amino acid combinations that are likely to be tolerated in the binding motifs P1, P4, and P7.
  • the figure shows that amino acids that are easily tolerated by P1 are A (Alanine), F (Phenylalanine), L ( Leucine), I (Isoleucine), P (Proline), S (Serine), V (Valine), and the amino acids that are easily tolerated by P2 are A, P, F, S, V, LN (Asparagine), R ( Arginine) and P7 has E (Glutami cAcid), D (Aspartic Acid), Q (Glutamine), P, N, I are easily tolerated.
  • a sequence consisting of 9 amino acid residues satisfying this combination was searched from the 558 amino acid sequence (SEQ ID NO: 5) of GPI, and 32 types of sequences (hereinafter referred to as “core epitope”) were extracted.
  • the extracted core epitopes are shown in “Table 2”.
  • Example 2 Identification of T cell epitope of GPI> Peptides containing 32 types of core epitopes extracted in Example 1 were synthesized, and T cell epitopes were screened by evaluating the ability of each peptide to induce cytokine production against T cells.
  • T (H) -17 a giant step from T (H) 1 and T (H) 2.” Nature Immunology, 2005, Vol.6, No.11 p.1069- 70). Therefore, in vitro screening of T cell epitopes was performed by evaluating the ability of each peptide to induce INF- ⁇ and IL-17 production on T cells.
  • CD4 + T cells and antigen-presenting cells isolated from the spleen of DBA / 1 mice in which arthritis was induced by immunization with recombinant GPI (rGPI) were treated with each peptide to produce INF- ⁇ and IL-17.
  • the amount was determined by measuring by ELISA. The procedure will be briefly described below.
  • RGPI was obtained by cloning human GPI cDNA (see SEQ ID NO: 4) into pGEX-4T3 plasmid (Pharmacia) and expressing it as a GST (glutathione S-transferase) fusion protein using E. coli.
  • GST glutthione S-transferase
  • the expressed GST-fused rGPI was purified using a gultathione-sepharose column.
  • CD4 + T cells in the cell dispersion were separated by magnetic cell sorting (MACS).
  • a device from Miltenyi Biotech was used for MACS.
  • Antigen-presenting cells were used after treating arthritis with spleen cells treated with mitomycin C.
  • CD4 + T cells and antigen-presenting cells were co-cultured at 5: 1, and each peptide was added to the culture solution at a concentration of 10 ⁇ M. After culturing for 24 hours after the addition, the culture supernatant was collected, and the production amounts of INF- ⁇ and IL-17 were measured using a commercially available ELISA kit (R & D Systems).
  • FIG. 2 Measured amounts of INF- ⁇ and IL-17 for 25 types of peptides are shown in “FIG. 2”.
  • Fig. (A) shows the measurement result of INF- ⁇
  • (B) shows the measurement result of IL-17.
  • the horizontal axis represents peptide No.
  • the vertical axis represents cytokine concentration (pg / ml).
  • INF- ⁇ and IL-17 in the culture supernatant showed remarkably high concentrations in cells treated with No. 118 and No. 125 peptides. From this, it was considered that the No. 118 and No. 125 peptides are likely to contain T cell epitopes.
  • the No. 118 and No. 125 peptides were re-synthesized in high purity as two peptides of 15 mer, respectively, and the same cytokine production inducing ability was evaluated.
  • the peptide was commissioned to Invitrogen and synthesized as a peptide having a purity of 90% or more.
  • the amino acid sequences of the synthesized peptides are shown in “Table 4”.
  • the No. 118 peptide has two core epitopes No. 22 and No. 23 shown in “Table 2”. Therefore, the No. 118 peptide was re-divided into a 15-mer peptide (No. 118-1) containing the No. 22 core epitope and a 15-mer peptide (No. 118-2) containing the No. 23 core epitope. Synthesized. Further, the No. 125 peptide has an amino acid sequence in which the N-terminal side partially overlaps with the No. 124 peptide shown in “Table 3”. However, since the No. 124 peptide itself did not show the ability to induce cytokine production (see FIG. 2), the No. 125 peptide had two types of 15mer peptides (No. 125) on the C-terminal side that did not overlap with the No. 124 peptide. -1, No.125-2) was re-synthesized.
  • FIG. 3 shows the measurement result of INF- ⁇
  • Fig. (A) shows the measurement result of INF- ⁇
  • (B) shows the measurement result of IL-17.
  • the horizontal axis represents peptide No.
  • the vertical axis represents cytokine concentration (pg / ml).
  • INF- ⁇ and IL-17 in the culture supernatant showed remarkably high concentrations in the cells treated with No. 118-1 peptide. From this, it was considered that the No.118-1 peptide contains the T cell epitope of GPI and the No.22 core epitope contained in the No.118-1 peptide is the main epitope (dominant epitope). .
  • Example 3 Arthritis induction experiment by dominant epitope> It was suggested that the GPI joint-inducing potential is that the No. 118-1 peptide, particularly the No. 22 core epitope, is a dominant epitope. Therefore, in this example, normal mice were used to evaluate the arthritis inducing ability of No. 118-1 peptide.
  • the evaluation result of the arthritis score is shown in “Fig. 4”.
  • the figure shows the change in arthritis score induced by immunization with No.118-1 peptide.
  • the horizontal axis represents the number of days after immunization, and the vertical axis represents the arthritis score.
  • FIG. 5 shows the external appearance image (A) and pathological image (C) of the joint 14 days after immunization.
  • (B) and (D) show an external finding image and a pathological finding image of a control mouse in which arthritis induction is not performed, respectively.
  • mice immunized with the No. 118-1 peptide exhibited marked bilateral polyarthritis from the 8th day after immunization, and this arthritis continued until the 28th day of observation (see FIG. 4).
  • arthritis could not be induced by immunization with No. 118-2, No. 125-1, or No. 125-2 peptide.
  • the No. 22 core epitope (SEQ ID NO: 1) and No. 118 peptide (SEQ ID NO: 3) having this binding motif can similarly induce arthritis. It was considered that typical arthritis can be induced easily and rapidly by immunizing animals with these peptides.
  • Example 2 It is the figure which showed the combination of the amino acid which is easy to accept
  • Example 2 it is a figure which shows the evaluation result of the cytokine production induction ability of 25 peptide synthesize
  • Fig. (A) shows the measurement result of INF- ⁇
  • (B) shows the measurement result of IL-17.
  • Example 2 it is a figure which shows the evaluation result of the cytokine production induction ability of 4 peptide resynthesized.
  • Fig. (A) shows the measurement result of INF- ⁇
  • and (B) shows the measurement result of IL-17.
  • Example 3 it is a figure which shows the score of the arthritis induced
  • the horizontal axis represents the number of days after peptide immunization, and the vertical axis represents the arthritis score.
  • FIGS. (B) and (D) show an external finding image and a pathological finding image of a control mouse in which arthritis induction is not performed, respectively.

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Abstract

La présente invention concerne un peptide arthritogène qui est utilisable dans l'immunisation d'un animal de façon à induire de façon commode une arthrite stable à un moment arbitraire, par comparaison avec un modèle existant utilisant un antigène spécifique de l'arthrite ou un modèle à médiation par un auto-anticorps. À cet effet, l'invention porte sur un peptide arthritogène contenant une séquence d'acides aminés présentée ci-après. [Formule chimique 4] Ile-N-N-Phe-N-N-Glu-N-N, où Ile désigne l'isoleucine ; Phe désigne la phénylalanine ; Glu désigne l'acide glutamique ; et N désigne un reste d'acides aminés arbitraire.
PCT/JP2008/071424 2008-02-01 2008-11-26 Peptide arthritogène Ceased WO2009096088A1 (fr)

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JP2008-022714 2008-02-01

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Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Japan College of Rheumatology Sokai - Gakujutsu Shukai - Kokusai Rheumatism Symposium Program - Shorokushu, 2006", vol. 50TH TO, article IWANAMI K. ET AL.: "GPI Yudosei Kansetsuen ni Okeru T-saibo Epitope no Kaiseki", pages: 157 *
"Japan College of Rheumatology Sokai · Gakujutsu Shukai · Kokusai Rheumatism Symposium Program · Shorokushu, 2008.4", vol. 52TH TO, article KEIICHI IWANAMI ET AL.: "Altered peptide ligand (APL) ni yoru GPI Yudosei Kansetsuen no Kogen Tokuiteki Seigyo", pages: 265 *
IWANAMI, K. ET AL.: "Arthritogenic T cell epitope in glucose-6-phosphate isomerase-induced arthritis", ARTHRITIS RES THER, vol. 10, no. 6, 7 November 2008 (2008-11-07), pages 1 - 12 *
MATSUMOTO I.: "Jiko Kogen Oyobi Kansetsuen Yudo Bunshi Shushoku ni yoru Jiko Kotai Sansei Seigyo", ARATANA SHINDAN - CHIRYOHO KAIHATSU NO TAME NO MEN'EKIGAKUTEKI SHUHO NO KAIHATSU NI KANSURU KENKYU HEISEI 17 NENDO SOKATSU - BUNTAN KENKYU HOKOKUSHO, 2006, pages 24 - 26 *
SCHUBERT, D. ET AL.: "Immunization with glucose- 6-phosphate isomerase induces T cell-dependent peripheral polyarthritis in genetically unaltered mice", J IMMUNOL, vol. 172, no. 7, 2004, pages 4503 - 4509 *
TAKAYUKI SUMIDA: "Analog Peptide ni yoru Kogen Tokuiteki Men'eki Bunshi Seigyoho no Kaihatsu ni Kansuru Kenkyu", ARATANA SHINDAN · CHIRYOHO KAIHATSU NO TAME NO MEN'EKIGAKUTEKI SHUHO NO KAIHATSU NI KANSURU KENKYU HEISEI 17 NENDO SOKATSU · BUNTAN KENKYU HOKOKUSHO, 2006, pages 7 - 9 *
TAKAYUKI SUMIDA: "Analog Peptide ni yoru Kogen Tokuiteki Men'eki Bunshi Seigyoho no Kaihatsu ni Kansuru Kenkyu", ARATANA SHINDAN · CHIRYOHO KAIHATSU NO TAME NO MEN'EKIGAKUTEKI SHUHO NO KAIHATSU NI KANSURU KENKYU HEISEI 19 NENDO SOKATSU · BUNTAN KENKYU HOKOKUSHO, March 2008 (2008-03-01), pages 7 - 9 *

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