WO2008017963A4 - Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof - Google Patents

Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof Download PDF

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Publication number
WO2008017963A4
WO2008017963A4 PCT/IB2007/003542 IB2007003542W WO2008017963A4 WO 2008017963 A4 WO2008017963 A4 WO 2008017963A4 IB 2007003542 W IB2007003542 W IB 2007003542W WO 2008017963 A4 WO2008017963 A4 WO 2008017963A4
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WO
WIPO (PCT)
Prior art keywords
abm
seq
heavy chain
cancer
kabat position
Prior art date
Application number
PCT/IB2007/003542
Other languages
French (fr)
Other versions
WO2008017963A2 (en
WO2008017963A3 (en
Inventor
Pablo Umana
Ekkehard Mossner
Original Assignee
Glycart Biotechnology Ag
Pablo Umana
Ekkehard Mossner
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP07825698.9A priority Critical patent/EP2057192B1/en
Priority to MX2009001382A priority patent/MX2009001382A/en
Application filed by Glycart Biotechnology Ag, Pablo Umana, Ekkehard Mossner filed Critical Glycart Biotechnology Ag
Priority to CN200780037124.5A priority patent/CN101535343B/en
Priority to BRPI0716639A priority patent/BRPI0716639B8/en
Priority to CA2660584A priority patent/CA2660584C/en
Priority to ES07825698T priority patent/ES2424388T3/en
Priority to KR1020097004840A priority patent/KR101452530B1/en
Priority to JP2009523372A priority patent/JP5421105B2/en
Priority to AU2007282923A priority patent/AU2007282923B2/en
Publication of WO2008017963A2 publication Critical patent/WO2008017963A2/en
Publication of WO2008017963A3 publication Critical patent/WO2008017963A3/en
Priority to IL196732A priority patent/IL196732A0/en
Priority to NO20090406A priority patent/NO20090406L/en
Priority to ZA2009/01590A priority patent/ZA200901590B/en
Publication of WO2008017963A4 publication Critical patent/WO2008017963A4/en
Priority to HK09110543.2A priority patent/HK1131163A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/461—Igs containing Ig-regions, -domains or -residues form different species
    • C07K16/464—Igs containing CDR-residues from one specie grafted between FR-residues from another
    • 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
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • 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
    • C07K2317/565—Complementarity determining region [CDR]
    • 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
    • C07K2317/567—Framework region [FR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—Increased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]

Abstract

The present invention relates to antigen binding molecules (ABMs). In particular embodiments, the present invention relates to recombinant monoclonal antibodies, including chimeric, primatized or humanized antibodies specific for human EGFR. In addition, the present invention relates to nucleic acid molecules encoding such ABMs, and vectors and host cells comprising such nucleic acid molecules. The invention further relates to methods for producing the ABMs of the invention, and to methods of using these ABMs in treatment of disease. In addition, the present invention relates to ABMs with modified glycosylation having improved therapeutic properties, including antibodies with increased Fc receptor binding and increased effector function.

Claims

AMENDED CLAIMS received by the International Bureau on 05 November 2008 (05.11.08)
1. An antigen binding molecule (ABM), comprising one or more specificity determining residues (SDRs) of one or more complementarity determining regions (CDRs) of the rat ICR62 monoclonal antibody, and a sequence derived from a heterologous polypeptide, wherein said ABM specifically binds to EGFR, but does not cause a clinically significant level of toxicity when administered to a subject in a therapeutically effective amount and wherein said ABM does not comprise a sequence selected from the group consisting of SEQ ID NO:3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ DD NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 51, and SEQ ID NO: 121.
2. The ABM of claim 1, wherein said one or more SDRs are in one or more heavy chain CDRs.
3. The ABM of claim 2, wherein said one or more heavy chain SDRs is selected from the group consisting of phenylalanine at Kabat position 29, asparagine at Kabat position 52, tyrosine at Kabat position 56, and valine at Kabat position 100b.
4. The ABM of claim 3, wherein said one or more heavy chain SDRs comprise tyrosine at Kabat position 56 and valine at Kabat position 100b.
5. The ABM of claim 3, wherein one or more heavy chain SDRs are phenylalanine at Kabat position 29, asparagine at Kabat position 52, tyrosine at Kabat position 56 and valine at Kabat position 100b.
6. The ABM of claim 1, wherein said one or more SDRs are in one or more light chain CDRs.
7. The ABM of claim 6, wherein said one or more light chain SDRs comprise asparagine at Kabat position 50.
8. The ABM of claim 6, wherein said one or more light chain SDRs comprise asparagine at Kabat position 34 and asparagine at Kabat position 50. 147
30. An isolated polypeptide encoding an immunoglobulin heavy chain variable region comprising modified heavy chain CDRs of the rat ICR62 monoclonal antibody and a heavy chain framework region derived from one or more human germline variable region gene sequences, wherein said modified heavy chain CDRs comprise one or more amino acid substitutions at a Kabat position selected from the group consisting of 27, 28, 29, 30, 31, 32, 33, 34, 35, 52, 52a, 53, 54, 55, 57, 58, 59, 60, 61, 62, 63, 64, 65, 95, 96, 97, 98, 99, 100, 100a, 101, 102, and any combination thereof, and wherein said polypeptide, as part of an antigen binding molecule, specifically binds to human EGFR but does not cause a clinically significant level of toxicity when administered to a subject in a therapeutically effective amount.
31. The polypeptide of claim 30, wherein said modified heavy chain CDRs comprise one or more amino acid substitutions at Kabat positions 27, 28, 29, 31, 52, 53, 54, 58, and 102.
32. The polypeptide of claim 30, wherein said modified heavy chain CDRs comprise one or more amino acid substitutions at Kabat positions 27, 28, 31, 53, 54, and 58.
33. The polypeptide of claim 30, wherein said modified heavy chain CDRs comprise amino acid substitutions at all positions within the Kabat and Chothia heavy chain CDRs except the SDRs.
34. The polypeptide of claim 30, wherein said modified heavy chain CDRs comprise amino acid substitutions at all positions within the Kabat and Chothia heavy chain CDRs except Kabat positions 29, 52, 56, and 100b.
35. An isolated polypeptide encoding an immunoglobulin light chain variable region comprising modified light chain CDRs of the rat ICR62 monoclonal antibody and a light chain framework region derived from one or more human germline variable region gene sequences, wherein said modified light chain CDRs comprise one or more amino acid substitutions at a Kabat position selected from the group consisting of 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 51, 52, 53, 54, 55, 56, 89, 90, 91, 92, 93, 94, 95, 96, 97, and any combination thereof, and wherein said polypeptide, as part of an antigen binding molecule, specifically binds to human EGFR.
36. The polypeptide of claim 35, wherein said modified light chain CDRs comprise amino acid substitutions at all positions within the Kabat and Chothia light chain CDRs, except the SDRs. 148
48. An ABM according to any of claims 1-29 or 47, wherein said ABM comprises an Fc region.
49. The ABM of of claim 48, wherein sad Fc region has been glycoengineered to have an altered oligosaccharide structure.
50. The ABM of claim 49, wherein said Fc region has a reduced number of fucose residues as compared to a corresponding nonglycoengineered ABM.
51. The ABM of claim 48, wherein said Fc region has been glycoengineered to have increased effector function or increased Fc receptor binding affinity compared to a corresponding nonglycoengineered ABM.
52. The ABM of any of olaims 1 29 or 46 51, whoroin said ΛBM does not cause α clinically significant level of toxicity when administered to a subject in a therapeutically offootive amount.
53. A composition comprising the ABM of any of claims 1-29 or 46-52 and a pharmaceutically acceptable carrier.
54. A method of targeting cells expressing EGFR in a subject comprising administering to said subject the composition of claim 53.
55. The method of claim 54, wherein said cells over-express EGFR.
56. The method of claim 54, wherein said method is performed to treat a disorder treatable by blocking EGFR-mediated cell-signaling in said subject.
57. The ABM of any of claims 1-29 or 46-52 for use in the manufacture of a medicament for the treatment of a disorder treatable by blocking EGFR-mediated cell signaling.
58. Use of the ABM of any of claims 1-29 or 46-52 in the manufacture of a medicament for the treatment of a disorder treatable by blocking EGFR-mediated cell signaling.
59. The method of claim 54, the ABM of claim 57, or the use of claim 58, wherein said disorder is a cell proliferation disorder.
60. The method, ABM, or use of claim 59, wherein said cell proliferation disorder is cancer.
61. The method, ABM, or use of claim 60, wherein said cancer is selected from the group consisting of breast cancer, bladder cancer, head & neck cancer, skin cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, kidney cancer, and brain cancer.
62. (New) The ABM of claim 39 or claim 40, wherein said antigen binding molecule does not cause a clinically significant level of toxicity when administered to a subject in a therapeutically effective amount.
63. (New) The ABM of any of claims 1, 30, 39 or 40, wherein said therapeutically effective amount results in a serum concentration of said ABM of between about 1 μg/ml and about 500 μg/ml for a period of at least 4 weeks.
64. (New) The ABM of claim 63, wherein said therapeutically effective amount results in a serum concentration of said ABM of between about 1 μg/ml and about 100 μg/ml for a period of at least 4 weeks.
65. (New) The ABM of any of claims 1, 30, 39 or 40, wherein said therapeutically effective amount of said ABM is from about 1.0 mg/kg to about 15 mg/kg.
66. (New) The ABM of any of claims 1, 30, 39, or 40, wherein the toxicity of said ABM is measured using blood chemistry values or histopathological indicators.
PCT/IB2007/003542 2006-08-09 2007-08-09 Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof WO2008017963A2 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
AU2007282923A AU2007282923B2 (en) 2006-08-09 2007-08-09 Antigen binding molecules that bind EGFR, vectors encoding same, and uses thereof
JP2009523372A JP5421105B2 (en) 2006-08-09 2007-08-09 Antigen binding molecule that binds to EGFR, vector encoding the same, and use thereof
CN200780037124.5A CN101535343B (en) 2006-08-09 2007-08-09 In conjunction with the antigen binding molecules of EGFR, its carrier of encoding, and application
MX2009001382A MX2009001382A (en) 2006-08-09 2007-08-09 Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof.
CA2660584A CA2660584C (en) 2006-08-09 2007-08-09 Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof
ES07825698T ES2424388T3 (en) 2006-08-09 2007-08-09 Antigen-binding molecules that bind to EGFR, vectors that encode them, and uses thereof
KR1020097004840A KR101452530B1 (en) 2006-08-09 2007-08-09 Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof
EP07825698.9A EP2057192B1 (en) 2006-08-09 2007-08-09 Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof
BRPI0716639A BRPI0716639B8 (en) 2006-08-09 2007-08-09 antigen-binding molecule, its method of production, composition and its uses.
IL196732A IL196732A0 (en) 2006-08-09 2009-01-26 Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof
NO20090406A NO20090406L (en) 2006-08-09 2009-01-28 Antigen-binding molecules that bind EGFR, vectors encoding these, and uses thereof
ZA2009/01590A ZA200901590B (en) 2006-08-09 2009-03-05 Antigen binding molecules that bind egfr,vectors encoding same,and uses thereof
HK09110543.2A HK1131163A1 (en) 2006-08-09 2009-11-12 Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US83637106P 2006-08-09 2006-08-09
US60/836,371 2006-08-09

Publications (3)

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WO2008017963A2 WO2008017963A2 (en) 2008-02-14
WO2008017963A3 WO2008017963A3 (en) 2008-11-06
WO2008017963A4 true WO2008017963A4 (en) 2009-03-12

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PCT/IB2007/003542 WO2008017963A2 (en) 2006-08-09 2007-08-09 Antigen binding molecules that bind egfr, vectors encoding same, and uses thereof

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US (5) US7662377B2 (en)
EP (2) EP2444422B1 (en)
JP (1) JP5421105B2 (en)
KR (1) KR101452530B1 (en)
CN (1) CN101535343B (en)
AR (1) AR062223A1 (en)
AU (1) AU2007282923B2 (en)
BR (1) BRPI0716639B8 (en)
CA (1) CA2660584C (en)
CL (1) CL2007002318A1 (en)
ES (2) ES2424388T3 (en)
HK (1) HK1131163A1 (en)
IL (1) IL196732A0 (en)
MX (1) MX2009001382A (en)
NO (1) NO20090406L (en)
PE (2) PE20081132A1 (en)
RU (1) RU2457219C2 (en)
TW (1) TWI418566B (en)
WO (1) WO2008017963A2 (en)
ZA (1) ZA200901590B (en)

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