CA2200868A1 - Cdr-grafted type iii anti-cea humanized mouse monoclonal antibodies - Google Patents

Cdr-grafted type iii anti-cea humanized mouse monoclonal antibodies

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Publication number
CA2200868A1
CA2200868A1 CA002200868A CA2200868A CA2200868A1 CA 2200868 A1 CA2200868 A1 CA 2200868A1 CA 002200868 A CA002200868 A CA 002200868A CA 2200868 A CA2200868 A CA 2200868A CA 2200868 A1 CA2200868 A1 CA 2200868A1
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Prior art keywords
seq
region
human antibody
amino acids
occurs naturally
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CA002200868A
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French (fr)
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CA2200868C (en
Inventor
Hans J. Hansen
Kathryn L. Armour
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Immunomedics Inc
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Hans J. Hansen
Kathryn L. Armour
Immumomedics, Inc.
Immunomedics, Inc.
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Application filed by Hans J. Hansen, Kathryn L. Armour, Immumomedics, Inc., Immunomedics, Inc. filed Critical Hans J. Hansen
Publication of CA2200868A1 publication Critical patent/CA2200868A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3007—Carcino-embryonic Antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6853—Carcino-embryonic antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Abstract

A humanized monoclonal antibody, comprising the complementarity-determining regions of a parental murine Class III, anti-CEA monoclonal antibody engrafted to the framework regions of a heterologous antibody, wherein the humanized monoclonal antibody retains the binding specificity of, but is less immunogenic in a heterologous host than, the parental murine monoclonal antibody. A preferred murine Class III, anti-CEA monoclonal antibody is the MN-14 antibody and the preferred heterologous antibody is from a human. Also provided are DNA constructs and vectors for producing the humanized monoclonal antibodies, and diagnostic and therapeutic conjugates using same.

Claims (34)

1. A humanized monoclonal antibody, comprising the complementarity-determining regions (CDRs) of a parental murine Class III anti-CEA Mn14 monoclonal antibody engrafted to the framework regions (FRs) of a human antibody, wherein said humanized antibody retains the specificity of said Mn14 monoclonal antibody but is less immunogenic in a human subject than is said parental murine Mn14 monoclonal antibody, and wherein said humanized monoclonal antibody is selected from the mutation variant group consisting of KLHuVHAIG/HuVK (SEQ. ID NO.
13), KLHuVHAIGA/HuVK (SEQ. ID NO. 14) AND KLHuVHAIGAY/HuVK (SEQ.
ID NO. 15)
2. A humanized monoclonal antibody according to claim 1, wherein:
(a) the light chain variable regions are characterized by the formula:
FRL1- CDRL1- FRL2-CDRL2-FRL3-CDRL3-FRL4, wherein each FR is a different framework region of a human antibody, and each CDR is a different complementarity determining region of the light chain of MN-14; and, (b) the heavy chain variable regions are characterized by the formula:
FRH1-CDRH1-FRH2-CDRH2-FRH3-CDRH3-FRH4, wherein each FR is a different framework region of a human antibody and each CDR is a different complementarity determining region of the heavy chain of Mn14.
3. A humanized monoclonal antibody according to claim 2, wherein the amino acid sequence of:
CDRL1 is KASQD VGTSV A (SEQ. ID. NO. 20);
CDRL2 is WTSTR HT (SEQ. ID. NO. 21);
CDRL3 is QQYSL YRS (SEQ. ID. NO. 22);
CDRH1 is TYWMS (SEQ. ID. NO. 23);
CDRH2 is EIHPD SSTIN YAPSL KD (SEQ. ID NO. 24); and, CDRH3 is LYFGF PWFAY (SEQ. ID NO. 25).
4. A humanized monoclonal antibody according to claim 2, wherein:

FRL1 comprises a region of about 23 amino acids that occurs naturally in the FRL1 of a human antibody;
FRL2 comprises a region of about 15 amino acids that occurs naturally in the FRL22 of a human antibody;
FRL3 comprises a region of about 32 amino acids that occurs naturally in the FRL3 of a human antibody;
FRL4 comprises a region of about 10 amino acids that occurs naturally in the FRL4 of a human antibody;
FRH1 comprises a region of 28-32 amino acids that occurs naturally in the FRH1 of a human antibody;
FRH2 comprises a region of 12-16 amino acids that occurs naturally in the FRH2 of a human antibody;
FRH3 comprises a region of 30-34 amino acids that occurs naturally in the FRH3 of a human antibody; and FRH4 comprises a region of 9-13 amino acids that occurs naturally in the FRH4 of a human antibody.
5. A humanized monoclonal antibody according to claim 4, wherein the amino acid sequence of:
FRL1 is DIQLT QSPSS LSASV GDRVT ITC (SEQ. ID NO. 26);
FRL2 is WYQQK PGKAP KLLIY (SEQ. ID NO. 27);
FRL3 is GVP(S or D)R FSGS(G or V) SGTDF TFTIS SLQPE DIATY YC
(SEQ. ID NO. 28);
FRL4 is FGQGT KVIEK (SEQ. ID NO. 29);
FRH1 is EVQLV ESGGG VVQPG RSLRL SCSSS GFDFT (SEQ. ID NO. 30), EVQLV ESGGG VVQPG RSLRL SCSAS GFDFT (SEQ. ID NO. 31) or QVQLQ ESGPG LVRPS QTLSL TCTSS GFDFT (SEQ. ID NO. 32);
FRH2 is WVRQA PGKGL EWVA (SEQ. ID NO. 33), WVRQA PGKGL EWIA (SEQ. ID NO. 34) or WVRQP PGRGL EWIA (SEQ. ID NO. 35);
FRH3 is RFTIS RDNSK NTLFL QMDSL RPEDT GVYFC AS (SEQ. ID NO. 36), RFTIS RDNAK NTLFL QMDSL RPEDT GVYFC AS (SEQ. ID NO. 37) or RVTML RDTSK NGSFL RLSSV TAADT AVYYC AS (SEQ. ID NO. 38); and FRH4 is WGQGT PVTVS S (SEQ. ID NO. 39) or WGQGT TVTVS S (SEQ. ID NO. 40);
and wherein C may be in the sulfhydryl or disulfide form.
6. A humanized monoclonal antibody according to claim 5, wherein the amino acid sequence of:
CDRL1 is KASQD VGTSV A (SEQ. ID NO. 20);
CDRL2 is WTSTR HT (SEQ. ID NO. 21);
CDRL3 is QQYSL YRS (SEQ. ID NO. 22);
CDRH1 is TYWMS (SEQ. ID NO. 23);
CDRH2 is EIHPD SSTIN YAPSL KD (SEQ. ID NO. 24); and CDRH3 is LYFGF PWFAY (SEQ. ID NO. 25).
7. A conjugate comprising a diagnostic or therapeutic agent bound to a humanized monoclonal antibody of claim 1,
8. A conjugate according to claim 7, wherein in said monoclonal antibody:
(a) the light chain variable regions are characterized by the formula:
FRL1- CDRL1- FRL2 - CDRL2 - FRL3 - CDRL3 - FRL4, wherein each FR is a different framework region of a human antibody, and each CDR is a different complementarity determining region of the light chain of Mn14; and, (b) the heavy chain variable regions are characterized by the formula:
FRH1-CDRH1-FRH2-CDRH2-FRH3-CDRH3-FRH4, wherein each FR is a different framework region of a human antibody, and each CDR is a different complementarity determining region of the heavy chain of Mn14.
9. A conjugate according to claim 8, wherein the amino acid sequence of:
CDRL1 is KASQD VGTSV A (SEQ. ID NO. 20);
CDRL2 is WTSTR HT (SEQ. ID NO. 21);
CDRL3 is QQYSL YRS (SEQ. ID NO. 22);
CDRH1 is TYWMS (SEQ. ID NO. 23);
CDRH2 is EIHPD SSTIN YAPSL KD (SEQ. ID NO. 24); and, CDRH3 is LYFGF PWFAY (SEQ. ID NO. 25).
10. A conjugate according to claim 8, wherein:
FRL1 comprises a region of about 23 amino acids that occurs naturally in the FRL1 of a human antibody;
FRL2 comprises a region of about 15 amino acids that occurs naturally in the FRL22 of a human antibody;
FRL3 comprises a region of about 32 amino acids that occurs naturally in the FRL33 of a human antibody;
FRL4 comprises a region of about 10 amino acids that occurs naturally in the FRL4 of a human antibody;
FRH1 comprises a region of 28-32 amino acids that occurs naturally in the FRH1 of a human antibody;
FRH2 comprises a region of 12-16 amino acids that occurs naturally in the FRH2 of a human antibody;
FRH3 comprises a region of 30-34 amino acids that occurs naturally in the FRH3 of a human antibody; and FRH4 comprises a region of 9-13 amino acids that occurs naturally in the FRH4 of a human antibody.
11. A conjugate according to claim 10, wherein the amino acid sequence of:
FRL1 is DIQLT QSPSS LSASV GDRVT ITC (SEQ. ID NO . 26);
FRL2 is WYQQK PGKAP KLLIY (SEQ. ID NO. 27);
FRL3 is GVP(S or D)R FSGS(G or V) SGTDF TFTIS SLQPE DIATY YC
(SEQ. ID NO. 28);
FRL4 is FGQGT KVIEK (SEQ. ID NO. 29);
FRH1 is EVQLV ESGGG WQPG RSLRL SCSSS GFDFT (SEQ. ID NO. 30), EVQLV ESGGG VVQPG RSLRL SCSAS GFDFT (SEQ. ID NO. 31) or QVQLQ ESGPG LVRPS QTLSL TCTSS GFDFT (SEQ. ID NO. 32);
FRH2 is WVRQA PGKGL EWVA (SEQ. ID NO. 33), WVRQA PGKGL EWIA (SEQ. ID NO. 34) or WVRQP PGRGL EWIA (SEQ. ID NO. 35);
FRH3 is RFTIS RDNSK NTLFL QMDSL RPEDT GVYFC AS (SEQ. ID NO. 36), RFTIS RDNAK NTLFL QMDSL RPEDT GVYFC AS (SEQ. ID NO. 37) or RVTML RDTSK NGSFL RLSSV TAADT AVYYC AS (SEQ. ID NO. 38); and FRH4 is WGQGT PVTVS S (SEQ. ID NO. 39) or WGQGT TVTVS S (SEQ. ID NO. 40);
and wherein C may be in the sulfhydryl or disulfide form.
12. A conjugate according to Claim 11, wherein the amino acid sequence of:
CDRL1 is KASQD VGTSV A (SEQ. ID NO. 20);
CDRL2 is WTSTR HT (SEQ. ID NO. 21);
CDRL2 is QQYSL YRS (SEQ. ID NO. 22);
CDRH1 is TYWMS (SEQ. ID NO. 23);
CDRH2 is EIHPD SSTIN YAPSL KD (SEQ. ID NO. 24); and CDRH3 is LYFGF PWFAY (SEQ. ID NO. 25).
13. A conjugate according to claim 7 wherein said therapeutic agent comprises a cytotoxic agent.
14. A conjugate according to claim 7 wherein said diagnostic reagent comprises an imaging agent.
15. A method for diagnosing or treating a patient comprising the step of administering to said patient in an amount effective for diagnosis or treatment a conjugate comprising a diagnostic or therapeutic agent as described in any one of claims 7-14, inclusive.
16. An isolated, purified chimeric DNA that encodes the CDRs of the light and heavy chains of a parental Mn14 murine Class III anti-CEA monoclonal antibody and the FRs of a heterologous antibody, wherein said heterologous antibody can be derived from any species including human, wherein the antibody expressed by said chimeric DNA retains the Class III anti-CEA
binding specificity of said parental murine Class III anti-CEA
monoclonal antibody, but is less immunogenic in a heterologous subject than is said parental monoclonal antibody.
17. An isolated polynucleotide comprising a DNA sequence encoding the VH amino acid chain of the Mn14 monoclonal antibody as set out in Figure 1, and alleles, variants and mutations thereof.
18. A protein encoded by the DNA sequence of claim 17.
19. An isolated polynucleotide comprising a DNA sequence encoding the VK amino acid chain of the Mn14 monoclonal antibody as set out in Figure 2, and alleles, variants and mutations thereof.
20. A protein encoded by the DNA sequence of claim 19.
21. A vector for the expression of a humanized chimeric Mn14 heavy chain, said vector being designated pSVgptMn14MuVHHuIgG1, as described in Figure 3.
22. A vector for the expression of a humanized chimeric Mn14 kappa light chain, said vector being designated pSVhygMn14MuVKHuCK, as described in Figure 4.
23. A method for the expression of a humanized chimeric Mn14 monoclonal antibody, comprising the steps of:
(a) linearizing vectors pSVgptMn14MuVHHuIgG1 and pSVhygMn14MuVKHuCK;
(b) transfecting mammalian lymphoma cells with said linearized vectors;
(c) selecting said transfected cells for those expressing the gpt gene; and (d) selecting from said cells expressing said gpt gene cells secreting said humanized chimeric monoclonal antibody.
24. A vector for the expression of a reshaped humanized MN-14 variable heavy chain, designated pSVgptMn14NEWMHuIgG1, as described in Figure 3, wherein Mn14 amino acid residues at positions 24, 27, 28, 30, 71 and 94 are mutated into said variable heavy chain along with the CDRs of said Mn14 variable heavy chain.
25. A vector for the expression of a reshaped humanized Mn14 variable kappa light chain, designated pSVhgrMn14REIHuCK, as described in Figure 4, wherein Mn14 amino acid residues 24, 27, 28, 30, 71 and 94 are mutated into said variable kappa light chain along with the CDRs of said Mn14 variable kappa light chain.
26. An isolated, purified DNA according to claim 16, wherein:
(a) said light chain is characterized by a variable region of the formula:
FRL1- CDRL1- FRL2-CDRL2-FRL3-CDRL3-FRL4, wherein each FR is a different framework region of a human antibody, and each CDR is a different complementarity determining region of the light chain of Mn14; and, (b) the heavy chain variable regions are characterized by the formula:
FRH1-CDRH1-FRH2-CDRH2-FRH3-CDRH3-FRH4, wherein each FR is a different framework region of a human antibody and each CDR is a different complementarity determining region of the heavy chain of Mn14.
27. An isolated, purified DNA according to claim 26, wherein the amino acid sequence of:
CDRL1 is KASQD VGTSV A (SEQ. ID NO. 20);
CDRL2 is WTSTR HT (SEQ. ID NO. 21);
CDRL3 is QQYSL YRS (SEQ. ID NO. 22);
CDRH1 is TYWMS (SEQ. ID NO. 23);
CDRH2 is EIHPD SSTIN YAPSL KD (SEQ. ID NO. 24); and, CDRH3 is LYFGF PWFAY (SEQ. ID NO. 25).
28. An isolated, purified DNA according to claim 26, wherein:
FRL1 comprises a region of about 23 amino acids that occurs naturally in the FRL1 of a human antibody;
FRL2 comprises a region of about 15 amino acids that occurs naturally in the FRL22 of a human antibody;
FRL3 comprises a region of about 32 amino acids that occurs naturally in the FRL33 of a human antibody;
FRL4 comprises a region of about 10 amino acids that occurs naturally in the FRL4 of a human antibody;
FRH1 comprises a region of 28-32 amino acids that occurs naturally in the FRH1 of a human antibody;
FRH2 comprises a region of 12-16 amino acids that occurs naturally in the FRH2 of a human antibody;
FRH3 comprises a region of 30-34 amino acids that occurs naturally in the FRH3 of a human antibody; and, FRH4 comprises a region of 9-13 amino acids that occurs naturally in the FRH4 of a human antibody.
29. An isolated, purified DNA according to claim 28, wherein the amino acid sequence of:
FRL1 is DIQLT QSPSS LSASV GDRVT ITC (SEQ. ID NO. 26);

FRL2 is WYQQK PGKAP KLLIY (SEQ. ID NO. 27);
FRL3 is GVP(S or D)R FSGS(G or V) SGTDF TFTIS SLQPE DIATY YC6 (SEQ. ID NO. 28);
FRL4 is FGQGT KVIEK (SEQ. ID NO. 29);
FRH1 is EVQLV ESGGG VVQPG RSLRL SCSSS GFDFT (SEQ. ID NO. 30), EVQLV ESGGG VVQPG RSLRL SCSAS GFDFT (SEQ. ID NO. 31) or QVQLQ ESGPG LVRPS QTLSL TCTSS GFDFT (SEQ. ID NO. 32);
FRH2 is WVRQA PGKGL EWVA (SEQ. ID NO. 33), WVRQA PGKGL EWIA (SEQ. ID NO. 34) or WVRQP PGRGL EWIA (SEQ. ID NO. 35);
FRH3 is RFTIS RDNSK NTLFL QMDSL RPEDT GVYFC AS (SEQ. ID NO. 36), RFTIS RDNAK NTLFL QMDSL RPEDT GVYFC AS (SEQ. ID NO. 37) or RVTML RDTSK NGSFL RLSSV TAADT AVYYC AS (SEQ. ID NO. 38); and FRH4 is WGQGT PVTVS S (SEQ. ID NO. 39) or WGQGT TVTVS S (SEQ. ID NO. 40);
and wherein C may be in the sulfhydryl or disulfide form.
30. An isolated, purified DNA according to claim 29, wherein the amino acid sequence of:
CDRL1 is KASQD VGTSV A (SEQ. ID NO. 20);
CDRL2 is WTSTR HT (SEQ. ID NO. 21);
CDRL3 is QQYSL YRS (SEQ. ID NO. 22);
CDRH1 is TYWMS (SEQ. ID NO. 23) CDRH2 is EIHPD SSTIN YAPSL KD (SEQ. ID NO. 24); and CDRH3 is LYFGF PWFAY (SEQ. ID NO. 25).
31. Plasmid pSVgptMn14MuVHHuIgG1 of Figure 3 containing a chimeric reshaped gene.
32. Plasmid pSVhygMn14MuVKHuCK of Figure 4 containing a chimeric gene.
33. Transformed cells expressing the chimeric gene contained in the vector according to claim 31.
34. Transformed cells expressing the chimeric gene contained in the vector according to claim 32.
CA2200868A 1994-10-05 1995-09-28 Cdr-grafted type iii anti-cea humanized mouse monoclonal antibodies Expired - Lifetime CA2200868C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/318,157 1994-10-05
US08/318,157 US5874540A (en) 1994-10-05 1994-10-05 CDR-grafted type III anti-CEA humanized mouse monoclonal antibodies
PCT/US1995/011964 WO1996011013A1 (en) 1994-10-05 1995-09-28 Cdr-grafted type iii anti-cea humanized mouse monoclonal antibodies

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CA2200868A1 true CA2200868A1 (en) 1996-04-18
CA2200868C CA2200868C (en) 2010-04-13

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US (3) US5874540A (en)
EP (3) EP1736163B1 (en)
JP (3) JP3437580B2 (en)
AT (2) ATE464906T1 (en)
CA (1) CA2200868C (en)
DE (2) DE69536072D1 (en)
ES (1) ES2307294T3 (en)
WO (1) WO1996011013A1 (en)

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