Title:
ANTIBODY CONSTANT REGION VARIANT
Document Type and Number:
WIPO Patent Application WO/2010/107110
Kind Code:
A1
Abstract:
Disclosed is a constant region which can grant an antibody desirable properties particularly as a pharmaceutical by means of an amino acid sequence modification. The disclosed variant constant region considerably decreases heterogeneity by being used in antibody production. Namely, by introducing the disclosed modification into the heavy-chain constant regions of an antibody, homogeneity of the antibody can be maintained at a high level. More concretely, it is possible to prevent a decrease in homogeneity caused by disulfide bond linkage differences in the heavy chain of an antibody molecule. Furthermore, in a preferred embodiment, it is possible to prevent a decrease in homogeneity caused by a C-terminal deletion in a constant region of an antibody, and to improve the pharmacokinetics of the antibody.
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Inventors:
IGAWA TOMOYUKI (JP)
MAEDA ATSUHIKO (JP)
SHIRAIWA HIROTAKE (JP)
MAEDA ATSUHIKO (JP)
SHIRAIWA HIROTAKE (JP)
Application Number:
PCT/JP2010/054769
Publication Date:
September 23, 2010
Filing Date:
March 19, 2010
Export Citation:
Assignee:
CHUGAI PHARMACEUTICAL CO LTD (JP)
IGAWA TOMOYUKI (JP)
MAEDA ATSUHIKO (JP)
SHIRAIWA HIROTAKE (JP)
IGAWA TOMOYUKI (JP)
MAEDA ATSUHIKO (JP)
SHIRAIWA HIROTAKE (JP)
International Classes:
C07K16/00; A61K39/395; C12N15/09; C12P21/08
Domestic Patent References:
| WO2008145141A1 | 2008-12-04 | |||
| WO2005056606A2 | 2005-06-23 | |||
| WO2009041613A1 | 2009-04-02 | |||
| WO2009041621A1 | 2009-04-02 | |||
| WO1999058572A1 | 1999-11-18 | |||
| WO2005035756A1 | 2005-04-21 |
Foreign References:
| US20060194280A1 | 2006-08-31 | |||
| US20050261229A1 | 2005-11-24 | |||
| US20060194280A1 | 2006-08-31 | |||
| US20060194280A1 | 2006-08-31 |
Other References:
MARTINEZ T ET AL.: "Disulfide connectivity of human immunoglobulin G2 structural isoforms.", BIOCHEMISTRY, vol. 47, 2008, pages 7496 - 7508, XP002512403
JOHNSON KA ET AL.: "Cation exchange-HPLC and mass spectrometry reveal C-terminal amidation of an IgG1 heavy chain", ANALYTICAL BIOCHEMISTRY, vol. 360, 2007, pages 75 - 83, XP005725305
See also references of EP 2409991A4
JANICE M REICHERT, CLARK J ROSENSWEIG, LAURA B FADEN, MATTHEW C DEWITZ: "Monoclonal antibody successes in the clinic", NATURE BIOTECHNOLOGY, vol. 23, 2005, pages 1073 - 1078, XP002555770, DOI: doi:10.1038/nbt0905-1073
PAVLOU AK, BELSEY MJ., THE THERAPEUTIC ANTIBODIES MARKET, 2008
EUR. J. PHARM. BIOPHARM., vol. 59, no. 3, April 2005 (2005-04-01), pages 389 - 96
REDDY MP, KINNEY CA, CHAIKIN MA, PAYNE A, FISHMAN-LOBELL J, TSUI P, DAL MONTE PR, DOYLE ML, BRIGHAM-BURKE MR, ANDERSON D: "Elimination of Fc receptor-dependent effector functions of a modified IgG4 monoclonal antibody to human CD4", J. IMMUNOL., vol. 164, no. 4, 15 February 2000 (2000-02-15), pages 1925 - 33
GUYRE PM, GRAZIANO RF, GOLDSTEIN J, WALLACE PK, MORGANELLI PM, WARDWELL K, HOWELL AL.: "Increased potency of Fc-receptor-targeted antigens", CANCER IMMUNOL IMMUNOTHER, vol. 45, no. 3-4, November 1997 (1997-11-01), pages 146 - 8
STRAND V, KIMBERLY R, ISAACS JD.: "Biologic therapies in rheumatology: lessons learned, future directions", NAT. REV. DRUG DISCOV., vol. 6, no. L, January 2007 (2007-01-01), pages 75 - 92
GESSNER JE, HEIKEN H, TAMM A, SCHMIDT RE.: "The IgG Fc receptor family", ANN. HEMATOL., vol. 76, no. 6, June 1998 (1998-06-01), pages 231 - 48, XP002350430, DOI: doi:10.1007/s002770050396
COLE MS, ANASETTI C, TSO JY: "Human IgG2 variants of chimeric anti-CD3 are nonmitogenic to T cells", J. IMMUNOL., vol. 159, no. 7, 1 October 1997 (1997-10-01), pages 3613 - 21, XP002226664
CHAU LA, TSO JY, MELROSE J, MADRENAS J.: "HuM291 (Nuvion), a humanized Fc receptor-nonbinding antibody against CD3, anergizes peripheral blood T cells as partial agonist of the T cell receptor", TRANSPLANTATION, vol. 71, no. 7, 15 April 2001 (2001-04-15), pages 941 - 50, XP009186613, DOI: doi:10.1097/00007890-200104150-00020
ARMOUR KL, CLARK MR, HADLEY AG, WILLIAMSON LM.: "Recombinant human IgG molecules lacking Fcgamma receptor I binding and monocyte triggering activities", EUR. J. IMMUNOL., vol. 29, no. 8, August 1999 (1999-08-01), pages 2613 - 24, XP002501617, DOI: doi:10.1002/(SICI)1521-4141(199908)29:08<2613::AID-IMMU2613>3.0.CO;2-J
CHU GC, CHELIUS D, XIAO G, KHOR HK, COULIBALY S, BONDARENKO PV.: "Accumulation of Succinimide in a Recombinant Monoclonal Antibody in Mildly Acidic Buffers Under Elevated Temperatures", PHARM. RES., vol. 24, no. 6, 24 March 2007 (2007-03-24), pages 1145 - 56, XP019507226, DOI: doi:10.1007/s11095-007-9241-4
AJ CORDOBA, BJ SHYONG, D BREEN, RJ HARRIS: "Nonenzymatic hinge region fragmentation of antibodies in solution", J. CHROMATOGR. B. ANAL. TECHNOL. BIOMED. LIFE SCI., vol. 818, 2005, pages 115 - 121
JOHNSON KA, PAISLEY-FLANGO K, TANGARONE BS, PORTER TJ, ROUSE JC.: "Cation exchange-C and mass spectrometry reveal C-terminal amidation of an IgG1 heavy chain", ANAL. BIOCHEM., vol. 360, no. 1, 1 January 2007 (2007-01-01), pages 75 - 83, XP005725305, DOI: doi:10.1016/j.ab.2006.10.012
SHIRE SJ, SHAHROKH Z, LIU J.: "Challenges in the development of high protein concentration formulations", J. PHARM. SCI., vol. 93, no. 6, June 2004 (2004-06-01), pages 1390 - 402, XP009108986, DOI: doi:10.1002/jps.20079
HINTON PR, XIONG JM, JOHLFS MG, TANG MT, KELLER S, TSURUSHITA N.: "An engineered human IgGl antibody with longer serum half-life", J. IMMUNOL., vol. 176, no. 1, 1 January 2006 (2006-01-01), pages 346 - 56
GHETIE V, POPOV S, BORVAK J, RADU C, MATESOI D, MEDESAN C, OBER RJ, WARD ES: "Increasing the serum persistence of an IgG fragment by random mutagenesis", NAT. BIOTECHNOL., vol. 15, no. 7, July 1997 (1997-07-01), pages 637 - 40, XP000876642, DOI: doi:10.1038/nbt0797-637
WYPYCH J, LI M, GUO A, ZHANG Z, MARTINEZ T, ALLEN MJ, FODOR S, KELNER DN, FLYNN GC, LIU YD: "Human IgG2 antibodies display disulfide-mediated structural isofonns", J BIOL CHEM., vol. 283, no. 23, 6 June 2008 (2008-06-06), pages 16194 - 205, XP002512404, DOI: doi:10.1074/jbc.M709987200
DILLON TM, RICCI MS, VEZINA C, FLYNN GC, LIU YD, REHDER DS, PLANT M, HENKLE B, LI Y, DEECHONGKIT S, VARNUM B: "Structural and functional characterization of disulfide isoforms of the human IgG2 subclass", J BIOL CHEM., vol. 283, no. 23, 6 June 2008 (2008-06-06), pages 16206 - 15
MARTINEZ T, GUO A, ALLEN MJ, HAN M, PACE D, JONES J, GILLESPIE R, KETCHEM RR, ZHANG Y, BALLAND A.: "Disulfide connectivity of human immunoglobulin G2 structural isoforms", BIOCHEMISTRY, vol. 47, no. 28, 15 July 2008 (2008-07-15), pages 7496 - 508, XP002512403, DOI: doi:10.1021/BI800576C
"Sequences of Proteins of Immunological Interest", NIH PUBLICATION NO. 91-3242
EUR. J. HNMUNOL., vol. 29, no. 8, August 1999 (1999-08-01), pages 2613 - 24
HASHIMOTO-GOTOH, T., MIZUNO, T., OGASAHARA, Y., NAKAGAWA, M.: "An oligodeoxyribonucleotide-directed dual amber method for site-directed mutagenesis", GENE, vol. 152, 1995, pages 271 - 275, XP004042690, DOI: doi:10.1016/0378-1119(94)00750-M
ZOLLER, M. J., SMITH, M.: "Oligonucleotide-directed mutagenesis of DNA fragments cloned into M13 vectors", METHODS ENZYMOL., vol. 100, 1983, pages 468 - 500, XP001088749, DOI: doi:10.1016/0076-6879(83)00074-9
KRAMER, W., DRUTSA, V., JANSEN, H. W., KRAMER, B., PFLUGFELDER, M., FRITZ, H. J.: "The gapped duplex DNA approach to oligonucleotide-directed mutation construction", NUCLEIC ACIDS RES., vol. 12, 1984, pages 9441 - 9456, XP002026371
KRAMER W., FRITZ H. J.: "Oligonucleotide-directed construction of mutations via gapped duplex DNA Methods", ENZYMOL, vol. 154, 1987, pages 350 - 367
KUNKEL, T. A.: "Rapid and efficient site-specific mutagenesis without phenotypic selection", PROC. NATL. ACAD. SCI. USA, vol. 82, 1985, pages 488 - 492, XP002052322, DOI: doi:10.1073/pnas.82.2.488
NATURE BIOTECHNOLOGY, vol. 25, 2007, pages 563 - 565
NATURE BIOTECHNOLOGY, vol. 16, 1998, pages 773 - 777
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 255, 1999, pages 444 - 450
NATURE BIOTECHNOLOGY, vol. 23, 2005, pages 1159 - 1169
JOURNAL OF VIROLOGY, vol. 75, 2001, pages 2803 - 2809
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 308, 2003, pages 94 - 100
R. W. MALONE ET AL., PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 6077
P. L. FELGNER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 84, 1987, pages 7413
F. L. GRAHAM, A. J. VAN DER EB, VIROLOGY, vol. 52, 1973, pages 456 - 467
ANAL BIOCHEM., vol. 360, no. 1, 1 January 2007 (2007-01-01), pages 75 - 83
"Sequences of proteins of immunological interest", NIH PUBLICATION NO. 91-3242
NAT BIOTECHNOL., vol. 25, no. 12, December 2007 (2007-12-01), pages 1369 - 72
J BIOL CHEM., vol. 283, no. 23, 6 June 2008 (2008-06-06), pages 16194 - 205
J BIOL CHEM., vol. 283, no. 23, 6 June 2008 (2008-06-06), pages 16206 - 15
BIOCHEMISTRY, vol. 47, no. 28, 15 July 2008 (2008-07-15), pages 7496 - 508
NAT. REV. IMMUNOL., vol. 7, no. 9, September 2007 (2007-09-01), pages 715 - 25
NAT. BIOTECHNOL., vol. 25, no. 12, December 2007 (2007-12-01), pages 1369 - 72
J. BIOL. CHEM., vol. 282, no. 3, 19 January 2007 (2007-01-19), pages 1709 - 17
J. IMMUNOL., vol. 176, no. 1, 1 January 2006 (2006-01-01), pages 346 - 56
PROC. NATL. ACAD. SCI. USA., vol. 103, no. 49, 5 December 2006 (2006-12-05), pages 18709 - 14
INT. IMMUNOL., vol. 18, no. 12, December 2006 (2006-12-01), pages 1759 - 69
IMMUNOLOGY, vol. 88, 1996, pages 169 - 173
MOL IMMUNOL., vol. 31, no. 8, June 1994 (1994-06-01), pages 577 - 84
INFECTION AND IMMUNITY, March 2007 (2007-03-01), pages 1424 - 1435
NAT BIOTECHNOL., vol. 26, no. 2, February 2008 (2008-02-01), pages 209 - 11
J IMMUNOL., vol. 159, no. 7, 1 October 1997 (1997-10-01), pages 3372 - 82
MOL IMMUNOL., vol. 31, no. 15, October 1994 (1994-10-01), pages 1201 - 10
PROTEIN SCIENCE, vol. 4, 1995, pages 2411 - 2423
J. EXP. MED., vol. 180, no. 6, 1994, pages 2377 - 2381
PROC. NATL. ACAD. SCI. USA., vol. 99, no. 26, 2002, pages 16899 - 16903
J. IMMUNOL., vol. 169, no. 9, 1 November 2002 (2002-11-01), pages 5171 - 80
JOHNSON KA ET AL.: "Cation exchange-HPLC and mass spectrometry reveal C-terminal amidation of an IgG1 heavy chain", ANALYTICAL BIOCHEMISTRY, vol. 360, 2007, pages 75 - 83, XP005725305
See also references of EP 2409991A4
JANICE M REICHERT, CLARK J ROSENSWEIG, LAURA B FADEN, MATTHEW C DEWITZ: "Monoclonal antibody successes in the clinic", NATURE BIOTECHNOLOGY, vol. 23, 2005, pages 1073 - 1078, XP002555770, DOI: doi:10.1038/nbt0905-1073
PAVLOU AK, BELSEY MJ., THE THERAPEUTIC ANTIBODIES MARKET, 2008
EUR. J. PHARM. BIOPHARM., vol. 59, no. 3, April 2005 (2005-04-01), pages 389 - 96
REDDY MP, KINNEY CA, CHAIKIN MA, PAYNE A, FISHMAN-LOBELL J, TSUI P, DAL MONTE PR, DOYLE ML, BRIGHAM-BURKE MR, ANDERSON D: "Elimination of Fc receptor-dependent effector functions of a modified IgG4 monoclonal antibody to human CD4", J. IMMUNOL., vol. 164, no. 4, 15 February 2000 (2000-02-15), pages 1925 - 33
GUYRE PM, GRAZIANO RF, GOLDSTEIN J, WALLACE PK, MORGANELLI PM, WARDWELL K, HOWELL AL.: "Increased potency of Fc-receptor-targeted antigens", CANCER IMMUNOL IMMUNOTHER, vol. 45, no. 3-4, November 1997 (1997-11-01), pages 146 - 8
STRAND V, KIMBERLY R, ISAACS JD.: "Biologic therapies in rheumatology: lessons learned, future directions", NAT. REV. DRUG DISCOV., vol. 6, no. L, January 2007 (2007-01-01), pages 75 - 92
GESSNER JE, HEIKEN H, TAMM A, SCHMIDT RE.: "The IgG Fc receptor family", ANN. HEMATOL., vol. 76, no. 6, June 1998 (1998-06-01), pages 231 - 48, XP002350430, DOI: doi:10.1007/s002770050396
COLE MS, ANASETTI C, TSO JY: "Human IgG2 variants of chimeric anti-CD3 are nonmitogenic to T cells", J. IMMUNOL., vol. 159, no. 7, 1 October 1997 (1997-10-01), pages 3613 - 21, XP002226664
CHAU LA, TSO JY, MELROSE J, MADRENAS J.: "HuM291 (Nuvion), a humanized Fc receptor-nonbinding antibody against CD3, anergizes peripheral blood T cells as partial agonist of the T cell receptor", TRANSPLANTATION, vol. 71, no. 7, 15 April 2001 (2001-04-15), pages 941 - 50, XP009186613, DOI: doi:10.1097/00007890-200104150-00020
ARMOUR KL, CLARK MR, HADLEY AG, WILLIAMSON LM.: "Recombinant human IgG molecules lacking Fcgamma receptor I binding and monocyte triggering activities", EUR. J. IMMUNOL., vol. 29, no. 8, August 1999 (1999-08-01), pages 2613 - 24, XP002501617, DOI: doi:10.1002/(SICI)1521-4141(199908)29:08<2613::AID-IMMU2613>3.0.CO;2-J
CHU GC, CHELIUS D, XIAO G, KHOR HK, COULIBALY S, BONDARENKO PV.: "Accumulation of Succinimide in a Recombinant Monoclonal Antibody in Mildly Acidic Buffers Under Elevated Temperatures", PHARM. RES., vol. 24, no. 6, 24 March 2007 (2007-03-24), pages 1145 - 56, XP019507226, DOI: doi:10.1007/s11095-007-9241-4
AJ CORDOBA, BJ SHYONG, D BREEN, RJ HARRIS: "Nonenzymatic hinge region fragmentation of antibodies in solution", J. CHROMATOGR. B. ANAL. TECHNOL. BIOMED. LIFE SCI., vol. 818, 2005, pages 115 - 121
JOHNSON KA, PAISLEY-FLANGO K, TANGARONE BS, PORTER TJ, ROUSE JC.: "Cation exchange-C and mass spectrometry reveal C-terminal amidation of an IgG1 heavy chain", ANAL. BIOCHEM., vol. 360, no. 1, 1 January 2007 (2007-01-01), pages 75 - 83, XP005725305, DOI: doi:10.1016/j.ab.2006.10.012
SHIRE SJ, SHAHROKH Z, LIU J.: "Challenges in the development of high protein concentration formulations", J. PHARM. SCI., vol. 93, no. 6, June 2004 (2004-06-01), pages 1390 - 402, XP009108986, DOI: doi:10.1002/jps.20079
HINTON PR, XIONG JM, JOHLFS MG, TANG MT, KELLER S, TSURUSHITA N.: "An engineered human IgGl antibody with longer serum half-life", J. IMMUNOL., vol. 176, no. 1, 1 January 2006 (2006-01-01), pages 346 - 56
GHETIE V, POPOV S, BORVAK J, RADU C, MATESOI D, MEDESAN C, OBER RJ, WARD ES: "Increasing the serum persistence of an IgG fragment by random mutagenesis", NAT. BIOTECHNOL., vol. 15, no. 7, July 1997 (1997-07-01), pages 637 - 40, XP000876642, DOI: doi:10.1038/nbt0797-637
WYPYCH J, LI M, GUO A, ZHANG Z, MARTINEZ T, ALLEN MJ, FODOR S, KELNER DN, FLYNN GC, LIU YD: "Human IgG2 antibodies display disulfide-mediated structural isofonns", J BIOL CHEM., vol. 283, no. 23, 6 June 2008 (2008-06-06), pages 16194 - 205, XP002512404, DOI: doi:10.1074/jbc.M709987200
DILLON TM, RICCI MS, VEZINA C, FLYNN GC, LIU YD, REHDER DS, PLANT M, HENKLE B, LI Y, DEECHONGKIT S, VARNUM B: "Structural and functional characterization of disulfide isoforms of the human IgG2 subclass", J BIOL CHEM., vol. 283, no. 23, 6 June 2008 (2008-06-06), pages 16206 - 15
MARTINEZ T, GUO A, ALLEN MJ, HAN M, PACE D, JONES J, GILLESPIE R, KETCHEM RR, ZHANG Y, BALLAND A.: "Disulfide connectivity of human immunoglobulin G2 structural isoforms", BIOCHEMISTRY, vol. 47, no. 28, 15 July 2008 (2008-07-15), pages 7496 - 508, XP002512403, DOI: doi:10.1021/BI800576C
"Sequences of Proteins of Immunological Interest", NIH PUBLICATION NO. 91-3242
EUR. J. HNMUNOL., vol. 29, no. 8, August 1999 (1999-08-01), pages 2613 - 24
HASHIMOTO-GOTOH, T., MIZUNO, T., OGASAHARA, Y., NAKAGAWA, M.: "An oligodeoxyribonucleotide-directed dual amber method for site-directed mutagenesis", GENE, vol. 152, 1995, pages 271 - 275, XP004042690, DOI: doi:10.1016/0378-1119(94)00750-M
ZOLLER, M. J., SMITH, M.: "Oligonucleotide-directed mutagenesis of DNA fragments cloned into M13 vectors", METHODS ENZYMOL., vol. 100, 1983, pages 468 - 500, XP001088749, DOI: doi:10.1016/0076-6879(83)00074-9
KRAMER, W., DRUTSA, V., JANSEN, H. W., KRAMER, B., PFLUGFELDER, M., FRITZ, H. J.: "The gapped duplex DNA approach to oligonucleotide-directed mutation construction", NUCLEIC ACIDS RES., vol. 12, 1984, pages 9441 - 9456, XP002026371
KRAMER W., FRITZ H. J.: "Oligonucleotide-directed construction of mutations via gapped duplex DNA Methods", ENZYMOL, vol. 154, 1987, pages 350 - 367
KUNKEL, T. A.: "Rapid and efficient site-specific mutagenesis without phenotypic selection", PROC. NATL. ACAD. SCI. USA, vol. 82, 1985, pages 488 - 492, XP002052322, DOI: doi:10.1073/pnas.82.2.488
NATURE BIOTECHNOLOGY, vol. 25, 2007, pages 563 - 565
NATURE BIOTECHNOLOGY, vol. 16, 1998, pages 773 - 777
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 255, 1999, pages 444 - 450
NATURE BIOTECHNOLOGY, vol. 23, 2005, pages 1159 - 1169
JOURNAL OF VIROLOGY, vol. 75, 2001, pages 2803 - 2809
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 308, 2003, pages 94 - 100
R. W. MALONE ET AL., PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 6077
P. L. FELGNER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 84, 1987, pages 7413
F. L. GRAHAM, A. J. VAN DER EB, VIROLOGY, vol. 52, 1973, pages 456 - 467
ANAL BIOCHEM., vol. 360, no. 1, 1 January 2007 (2007-01-01), pages 75 - 83
"Sequences of proteins of immunological interest", NIH PUBLICATION NO. 91-3242
NAT BIOTECHNOL., vol. 25, no. 12, December 2007 (2007-12-01), pages 1369 - 72
J BIOL CHEM., vol. 283, no. 23, 6 June 2008 (2008-06-06), pages 16194 - 205
J BIOL CHEM., vol. 283, no. 23, 6 June 2008 (2008-06-06), pages 16206 - 15
BIOCHEMISTRY, vol. 47, no. 28, 15 July 2008 (2008-07-15), pages 7496 - 508
NAT. REV. IMMUNOL., vol. 7, no. 9, September 2007 (2007-09-01), pages 715 - 25
NAT. BIOTECHNOL., vol. 25, no. 12, December 2007 (2007-12-01), pages 1369 - 72
J. BIOL. CHEM., vol. 282, no. 3, 19 January 2007 (2007-01-19), pages 1709 - 17
J. IMMUNOL., vol. 176, no. 1, 1 January 2006 (2006-01-01), pages 346 - 56
PROC. NATL. ACAD. SCI. USA., vol. 103, no. 49, 5 December 2006 (2006-12-05), pages 18709 - 14
INT. IMMUNOL., vol. 18, no. 12, December 2006 (2006-12-01), pages 1759 - 69
IMMUNOLOGY, vol. 88, 1996, pages 169 - 173
MOL IMMUNOL., vol. 31, no. 8, June 1994 (1994-06-01), pages 577 - 84
INFECTION AND IMMUNITY, March 2007 (2007-03-01), pages 1424 - 1435
NAT BIOTECHNOL., vol. 26, no. 2, February 2008 (2008-02-01), pages 209 - 11
J IMMUNOL., vol. 159, no. 7, 1 October 1997 (1997-10-01), pages 3372 - 82
MOL IMMUNOL., vol. 31, no. 15, October 1994 (1994-10-01), pages 1201 - 10
PROTEIN SCIENCE, vol. 4, 1995, pages 2411 - 2423
J. EXP. MED., vol. 180, no. 6, 1994, pages 2377 - 2381
PROC. NATL. ACAD. SCI. USA., vol. 99, no. 26, 2002, pages 16899 - 16903
J. IMMUNOL., vol. 169, no. 9, 1 November 2002 (2002-11-01), pages 5171 - 80
Attorney, Agent or Firm:
SHIMIZU, Hatsushi et al. (JP)
Spring water Original aim (JP)
Spring water Original aim (JP)
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