Immunoglobulin variants

• US 5,821,337 A
• Filed: 08/21/1992
• Issued: 10/13/1998
• Est. Priority Date: 06/14/1991
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Presta, Leonard G., Carter, Paul J.
• Primary Examiner(s): Feisee, Lila
• Assistant Examiner(s): DAVIS, MINH TAM B
• Application Number:
  US07/934,373
• Time in Patent Office: 2,244 Days
• Field of Search: 530/387.3, 530/350, 530/388.2, 424/133.1
• US Class Current: 530/387.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 16/465 with additional modified FR-residues
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: G06F 15/00 Digital computers in general details G06F1/00 – G06F13/00; Data processing equipment in general

Abstract

Variant immunoglobulins, particularly humanized antibody polypeptides are provided, along with methods for their preparation and use. Consensus immunoglobulin sequences and structural models are also provided.

Claims

1. A humanized antibody comprising the light chain variable domain sequence in SEQ ID NO:

17.

2. A humanized antibody comprising the heavy chain variable domain sequence in SEQ ID NO:

20.

3. A humanized anti-CD3 antibody comprising the amino acid sequences in SEQ ID NO:

17 and SEQ ID NO;

20.

4. A variable domain of a humanized antibody comprising a heavy chain variable domain amino acid sequence within a sequence selected from the group consisting of:

SEQ ID NO;

23;

SEQ ID NO;

26;

SEQ ID NO;

27;

SEQ ID NO;

28;

SEQ ID NO;

29;

SEQ ID NO;

30;

SEQ ID NO;

31;

SEQ ID NO;

32;

SEQ ID NO;

33;

SEQ ID NO;

34;

SEQ ID NO;

35;

SEQ ID NO;

36;

SEQ ID NO;

37; and

SEQ ID NO;

38.

6. The variable domain of claim 4 comprising the variable domain sequence in SEQ ID NO:

46.

5. A variable domain of a humanized antibody comprising a light chain variable domain amino acid sequence within a sequence selected from the group consisting of SEQ ID NO:

25;

SEQ ID NO;

39; and

SEQ ID NO;

40.

7. The variable domain of claim 5 comprising the variable domain sequence in SEQ ID NO:

47.

8. A humanized anti-CD18 antibody comprising the variable domain sequence in SEQ ID NO:

46 and the variable domain sequence in SEQ ID NO;

47.

9. A polypeptide comprising the following amino acid sequence:

space="preserve" listing-type="tabular">__________________________________________________________________________DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLX.sup.1 SGVPSRFS GSX.sup.2 SGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID __________________________________________________________________________NO;

43),

wherein X¹ is E or Y and X² is R or G.

11. The polypeptide of claim 9 comprising the amino acid sequence:

DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSG SRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO;

41).

10. A polypeptide comprising the following amino acid sequence:

space="preserve" listing-type="tabular">__________________________________________________________________________EVQLVESGGGLVQPGGSLRLSCMSGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADS RFTISX.sup.3 DX.sup.4 SKNTX.sup.5 YLQMNSLRAEDTAVYYCX.sup.6 RWGGDGFYAMDX.sup.7 WGQGTLVTVSS SEQ ID NO;

44), __________________________________________________________________________

wherein X³ is A or R, X⁴ is T or D, X⁵ is A or L, X⁶ is S or A and X⁷ is V or Y.

12. The polypeptide of claim 10 comprising the amino acid sequence:

EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADS VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO;

42).

13. A humanized antibody comprising the heavy chain variable domain sequence:

space="preserve" listing-type="tabular">__________________________________________________________________________EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSV KGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDX.sup.1 WGQGTLVTVSS (SEQ ID NO;

48), __________________________________________________________________________

wherein X¹ is V or Y, and wherein the humanized antibody binds p185^HER2 more tightly than the non-human import antibody from which the CDR amino acid residues of the humanized antibody are derived.

14. The humanized antibody of claim 13 further comprising the light chain variable domain sequence:

space="preserve" listing-type="tabular">__________________________________________________________________________DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSG SRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO;

41). __________________________________________________________________________

15. A humanized anti-HER2 antibody which comprises the light chain variable domain amino acid sequence:

space="preserve" listing-type="tabular">__________________________________________________________________________DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGS RSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO;

41) __________________________________________________________________________

and the heavy chain variable domain amino acid sequence;

space="preserve" listing-type="tabular">__________________________________________________________________________EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSV KGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO;

42). __________________________________________________________________________