IP Library › Granted Patent US 7,811,785
Granted Patent B2
US 7,811,785 · App. 11/342,249 · Granted Oct 12, 2010

Anti-VEGF antibodies

Assignee: Genentech, Inc.
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Quick Facts
Patent No.
US 7,811,785
App. No.
11/342,249
Granted
Oct 12, 2010
Kind
B2
Abstract

Anti-VEGF antibodies and variants thereof, including those having high affinity for binding to VEGF, are disclosed. Also provided are methods of using phage display technology with naïve libraries to generate and select the anti-VEGF antibodies with desired binding and other biological activities. Further contemplated are uses of the antibodies in research, diagnostic and therapeutic applications.

Claims (158)

1. An isolated nucleic acid molecule encoding an antibody, or an Fab fragment thereof, wherein the antibody, or Fab fragment thereof, binds to human VEGF and comprises a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain comprises a CDR H1, CDR H2, and CDR H3, wherein:

(a) CDR H1 comprises the contiguous amino acid sequence DYWIH (SEQ ID NO: 261);

(b) CDR H2 comprises the contiguous amino acid sequence GITPAGGYTYYADSVKG (SEQ ID NO: 474); and

(c) CDR H3 comprises the contiguous amino acid sequence FVFFLPYAMDY (SEQ ID NO: 475);

and wherein the light chain variable domain comprises a CDR L1, CDR L2, and CDRL3, wherein:

(d) CDR L1 comprises the contiguous amino acid sequence RASQDVSTAVA (SEQ ID NO: 48);

(e) CDR L2 comprises the contiguous amino acid sequence SASFLYS (SEQ ID NO: 49; and

(f) CDR L3 comprises the contiguous amino acid sequence QQSYTTPPT (SEQ ID NO: 363).

2. The isolated nucleic acid molecule of claim 1 , wherein the antibody, or Fab fragment thereof, comprises the following amino acid sequence as its heavy chain variable domain (VH) and first heavy chain constant domain (CH1):

(SEQ ID NO. 29)

EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWVAG

ITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARFV

FFLPYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT

YICNVNHKPSNTKVDKKVEPKSCDKTH

and wherein the antibody comprises the following amino acid sequence as its light chain variable domain (VL):

(SEQ ID NO. 28)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYS

ASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPPTFGQ

GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV

DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG

LSSPVTKSFNRGEC.

3. An isolated nucleic acid molecule encoding an antibody, or an Fab fragment thereof, wherein the antibody, or Fab fragment thereof, binds to human VEGF and comprises a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain comprises a CDR H1, CDR H2, and CDR H3, wherein:

(a) CDR H1 comprises the contiguous amino acid sequence DYWIH (SEQ ID NO: 261);

(b) CDR H2 comprises the contiguous amino acid sequence GITPAGGYTYYADSVKG (SEQ ID NO: 474); and

(c) CDR H3 comprises the contiguous amino acid sequence FVFFLPYAMDY (SEQ ID NO: 475);

and wherein the light chain variable domain comprises a CDR L1, CDR L2, and CDRL3, wherein:

(d) CDR L1 comprises the contiguous amino acid sequence RASQDVSTAVA (SEQ ID NO: 48);

(e) CDR L2 comprises the contiguous amino acid sequence SASFLYS (SEQ ID NO: 49); and

(f) CDR L3 comprises the contiguous amino acid sequence KQGYANPWT (SEQ ID NO: 143).

4. The isolated nucleic acid molecule of claim 3 , wherein the antibody, or Fab fragment thereof, comprises the following amino acid sequence as its heavy chain variable domain (VH) and first heavy chain constant domain (CH1):

(SEQ ID NO. 29)

EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWV

AGITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC

ARFVFFLPYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH

and wherein the antibody comprises the following amino acid sequence as its light chain variable domain (VL):

(SEQ ID NO. 30)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLLYS

ASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCKQGYANPWTFGQ

GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV

DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG

LSSPVTKSFNRGEC.

5. An isolated nucleic acid molecule encoding an antibody, or an Fab fragment thereof, wherein the antibody, or Fab fragment thereof, binds to human VEGF and comprises a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain comprises a CDR H1, CDR H2, and CDR H3, wherein:

(a) CDR H1 comprises the contiguous amino acid sequence DYWIH (SEQ ID NO: 261);

(b) CDR H2 comprises the contiguous amino acid sequence GITPAGGYTYYADSVKG (SEQ ID NO: 474); and

(c) CDR H3 comprises the contiguous amino acid sequence FVFFLPYAMDY (SEQ ID NO: 475);

and wherein the light chain variable domain comprises a CDR L1, CDR L2, and CDRL3, wherein:

(d) CDR L1 comprises the contiguous amino acid sequence RASQDVSTAVA (SEQ ID NO: 48);

(e) CDR L2 comprises the contiguous amino acid sequence SASFLYS (SEQ ID NO: 49); and

(f) CDR L3 comprises the contiguous amino acid sequence QQGYGNPFT (SEQ ID NO: 52).

6. The isolated nucleic acid molecule of claim 5 , wherein the antibody, or Fab fragment thereof, comprises the following amino acid sequence as its heavy chain variable domain (VH) and first heavy chain constant domain (CH1):

(SEQ ID NO. 29)

EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWV

AGITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC

ARFVFFLPYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH

and wherein the antibody comprises the following amino acid sequence as its light chain variable domain (VL):

(SEQ ID NO. 32)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI

YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGNPF

TFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA

KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY

ACEVTHQGLSSPVTKSFNRGEC.

7. An isolated nucleic acid molecule encoding an antibody, or an Fab fragment thereof, wherein the antibody, or Fab fragment thereof, binds to human VEGF and comprises a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain comprises a CDR H1, CDR H2, and CDR H3, wherein:

(a) CDR H1 comprises the contiguous amino acid sequence ASWIH (SEQ ID NO: 936);

(b) CDR H2 comprises the contiguous amino acid sequence AIYPYSGYTNYADSVKG (SEQ ID NO. 941); and

(c) CDR H3 comprises the contiguous amino acid sequence WGHSTSPWAMDY (SEQ ID NO: 932)

and wherein the light chain variable domain comprises a CDR L1, CDR L2, and CDRL3, wherein:

(d) CDR L1 comprises the contiguous amino acid sequence RASQDVSTAVA (SEQ ID NO: 85);

(e) CDR L2 comprises the contiguous amino acid sequence SASFLYS (SEQ ID NO: 86); and

(f) CDR L3 comprises the contiguous amino acid sequence QQSYTTPPT (SEQ ID NO: 87).

8. The isolated nucleic acid molecule of claim 7 , wherein the antibody, or Fab fragment thereof, comprises the following amino acid sequence as its heavy chain variable domain (VH) and first heavy chain constant domain (CH1):

(SEQ ID NO. 38)

EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWV

GAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC

ARWGHSTSPWAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH,

and wherein the antibody comprises the following amino acid sequence as its light chain variable domain (VL):

(SEQ ID NO. 37)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI

YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPP

TFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA

KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY

ACEVTHQGLSSPVTKSFNRGEC.

9. An isolated nucleic acid molecule encoding an antibody, or an Fab fragment thereof, wherein the antibody, or Fab fragment thereof, binds to human VEGF and comprises a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain comprises a CDR H1, CDR H2, and CDR H3, wherein:

(a) CDR H1 comprises the contiguous amino acid sequence GSWIF (SEQ ID NO: 938);

(b) CDR H2 comprises the contiguous amino acid sequence AIWPFGGYTHYADSVKG (SEQ ID NO: 940);

(c) CDR H3 comprises the contiguous amino acid sequence WGHSTSPWAMDY (SEQ ID NO: 932);

and wherein the light chain variable domain comprises a CDR L1, CDR L2, and CDRL3, wherein:

(d) CDR L1 comprises the contiguous amino acid sequence RASQVIRRSLA (SEQ ID NO: 117);

(e) CDR L2 comprises the contiguous amino acid sequence AASNLAS (SEQ ID NO: 118); and

(f) CDR L3 comprises the contiguous amino acid sequence QQSNTSPLT (SEQ ID NO: 119).

10. The isolated nucleic acid molecule of claim 9 , wherein the antibody, or Fab fragment thereof, comprises the following amino acid sequence as its heavy chain variable domain (VH) and first heavy chain constant domain (CH1):

(SEQ ID NO. 41)

EVQLVESGGGLVQPGGSLRLSCAASGFSINGSWIFWVRQAPGKGLEWV

GAIWPFGGYTHYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC

ARWGHSTSPWAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH

and wherein the antibody comprises the following amino acid sequence as its light chain variable domain (VL):

(SEQ ID NO. 40)

DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLI

YAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPL

TFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA

KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY

ACEVTHQGLSSPVTKSFNRGEC.

11. An isolated nucleic acid molecule encoding an antibody, or an Fab fragment thereof, wherein the antibody, or Fab fragment thereof, binds to human VEGF and comprises a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain comprises a CDR H1, CDR H2, and CDR H3, wherein:

(a) CDR H1 comprises the contiguous amino acid sequence ASWIH (SEQ ID NO: 936);

(b) CDR H2 comprises the contiguous amino acid sequence AIYPYSGYTNYADSVKG (SEQ ID NO. 941);

(c) CDR H3 comprises the contiguous amino acid sequence WGHSTSPWAMDY (SEQ ID NO: 932);

and wherein the light chain variable domain comprises a CDR L1, CDR L2, and CDRL3, wherein:

(d) CDR L1 comprises the contiguous amino acid sequence RASQVIRRSLA (SEQ ID NO: 117);

(e) CDR L2 comprises the contiguous amino acid sequence AASNLAS (SEQ ID NO: 118); and

(f) CDR L3 comprises the contiguous amino acid sequence QQSNTSPLT (SEQ ID NO: 119).

12. The isolated nucleic acid molecule of claim 11 , wherein the antibody, or Fab fragment thereof, comprises the following amino acid sequence as its heavy chain variable domain (VH) and first heavy chain constant domain (CH1):

(SEQ ID NO. 38)

EVQLVESGGGLVQPGGSLRLSCAASGFTINASWIHWVRQAPGKGLEWV

GAIYPYSGYTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC

ARWGHSTSPWAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA

ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV

PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH

and wherein the antibody comprises the following amino acid sequence as its light chain variable domain (VL):

(SEQ ID NO. 39)

DIQMTQSPSSLSASVGDRVTITCRASQVIRRSLAWYQQKPGKAPKLLI

YAASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNTSPL

TFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA

KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY

ACEVTHQGLSSPVTKSFNRGEC.

13. An isolated nucleic acid molecule encoding an antibody, or an Fab fragment thereof, wherein the antibody, or Fab fragment thereof, binds to human VEGF and comprises a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable domain comprises a CDR H1, CDR H2, and CDR H3, wherein:

(a) CDR H1 comprises the contiguous amino acid sequence DYWIH (SEQ ID NO: 261);

(b) CDR H2 comprises the contiguous amino acid sequence GITPAGGYTYYADSVKG (SEQ ID NO: 474); and

(c) CDR H3 comprises the contiguous amino acid sequence FVFFLPYAMDY (SEQ ID NO: 475);

and wherein the light chain variable domain comprises a CDR L1, CDR L2, and CDRL3, wherein:

(d) CDR L1 comprises the contiguous amino acid sequence RASQDVSTAVA (SEQ ID NO: 48);

(e) CDR L2 comprises the contiguous amino acid sequence SASFLYS (SEQ ID NO: 49); and

(f) CDR L3 comprises the contiguous amino acid sequence QQGAGSPLT (SEQ ID NO: 68).

14. The isolated nucleic acid molecule of claim 13 , wherein the antibody, or Fab fragment thereof, comprises the following amino acid sequence as its heavy chain variable domain (VH) and first heavy chain constant domain (CH1):

(SEQ ID NO. 29)

EVQLVESGGGLVQPGGSLRLSCAASGFTISDYWIHWVRQAPGKGLEWV

AGITPAGGYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYC

ARFVFFLPYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA

LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP

SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH

and wherein the antibody comprises the following amino acid sequence as its light chain variable domain (VL):

(SEQ ID NO. 33)

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLI

YSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGAGSPL

TFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA

KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY

ACEVTHQGLSSPVTKSFNRGEC.

15. A vector comprising the nucleic acid of claim, 1 , 3 , 5 , 7 , 9 , or 11 .

16. A host cell comprising the vector of claim 15 .

17. A process of producing an antibody, or Fab fragment thereof, comprising culturing the host cell of claim 16 so that the antibody is produced.

18. The process of claim 17 , wherein the antibody is recovered from the host cell medium.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 14, 2008
From: FUH, GERMAINE; SIDHU, SACHDEV S.
To: GENENTECH, INC.
Reel/Frame 020650/0918 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 22, 2008
From: GERBER, HANS-PETER; LIANG, WEI-CHING; FELLOUSE, FREDERIC A.; WIESMANN, CHRISTIAN
To: GENENTECH, INC.
Reel/Frame 020421/0699 →
Continuity (8)
Continuation PCTUS200402466200 · Jul 30, 2004
Provisional Application 6049187700 · Aug 1, 2003
Provisional Application 6051649500 · Nov 1, 2003
Provisional Application 6057091200 · May 12, 2004
Provisional Application 6057123900 · May 13, 2004
Provisional Application 6057631500 · Jun 1, 2004
Provisional Application 6058075700 · Jun 18, 2004
Related Publication 20060280747A1 · Dec 14, 2006