Humanized immunoglobulins

• US 5,530,101 A
• Filed: 12/19/1990
• Issued: 06/25/1996
• Est. Priority Date: 12/28/1988
• Status: Expired due to Term

• Current Assignee: PDL BioPharma, Inc.
• Original Assignee: Protein Design Labs, Inc. (PDL BioPharma, Inc.)
• Inventors: Selick, Harold E., Queen, Cary L.
• Primary Examiner(s): Feisee, Lila
• Application Number:
  US07/634,278
• Time in Patent Office: 2,015 Days
• Field of Search: 424/85.8, 424/133.1, 424/143.1, 530/387, 530/388.22, 530/387.1, 530/387.3
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/087 Herpes simplex virus
• CPC Class Codes: C07K 16/088 Varicella-zoster virus
• CPC Class Codes: C07K 16/089 Cytomegalovirus
• CPC Class Codes: C07K 16/249 Interferons
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• 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 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/02 : containing a signal sequence
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

Novel methods for producing, and compositions of, humanized immunoglobulins having one or more complementarity determining regions (CDR'"'"'s) and possible additional amino acids from a donor immunoglobulin and a framework region from an accepting human immunoglobulin are provided. Each humanized immunoglobulin chain will usually comprise, in addition to the CDR'"'"'s, amino acids from the donor immunoglobulin framework that are, e.g., capable of interacting with the CDR'"'"'s to effect binding affinity, such as one or more amino acids which are immediately adjacent to a CDR in the donor immunoglobulin or those within about 3 Å as predicted by molecular modeling. The heavy and light chains may each be designed by using any one or all of various position criteria. When combined into an intact antibody, the humanized immunoglobulins of the present invention will be substantially non-immunogenic in humans and retain substantially the same affinity as the donor immunoglobulin to the antigen, such as a protein or other compound containing an epitope.

Claims

1. A humanized immunoglobulin having complementarity determining regions (CDRs) from a donor immunoglobulin and heavy and light chain variable region frameworks from human acceptor immunoglobulin heavy and light chain frameworks, which humanized immunoglobulin specifically binds to a human interleukin-2 receptor with an affinity constant of at least 10⁷ M^-1 and no greater than about two-fold that of the donor immunoglobulin, wherein the sequence of the humanized immunoglobulin heavy chain variable region framework is 65% to 95% identical to the sequence of the donor immunoglobulin heavy chain variable region framework.

2. A humanized immunoglobulin according to claim 1 which is an antibody comprising two light chain/heavy chain dimers.

3. A humanized immunoglobulin according to claim 1, which specifically binds to a human interleukin-2 receptor with an affinity of at least 10⁸ M^-1.

4. A humanized immunoglobulin according to claim 1, wherein said human interleukin-2 receptor is the p55 Tac interleukin-2 receptor.

5. A humanized immunoglobulin according to claim 1, wherein said human interleukin-2 receptor is the p75 interleukin-2 receptor.

6. A humanized immunoglobulin according to claim 1, wherein said donor immunoglobulin is the anti-Tac antibody.

7. A humanized immunoglobulin according to claim 1, wherein said acceptor immunoglobulin heavy and light chain frameworks are from the same human antibody.

8. A humanized immunoglobulin according to claim 7, wherein said human antibody is the Eu human antibody.

9. A humanized immunoglobulin according to claim 1 which is substantially pure.

10. A humanized immunoglobulin according to claim 1 that competitively inhibits the binding of interleukin-2 to said human interleukin-2 receptor.

11. A recombinant immunoglobulin which specifically binds to the p55 chain of the human IL-2 receptor, wherein the amino acid sequence of the mature light chain variable region is:

##STR1##

12. A recombinant immunoglobulin which specifically binds to the p55 chain of the human IL-2 receptor, wherein the amino acid sequence of the mature heavy chain variable region is:

##STR2##

13. An immunoglobulin which specifically binds to the p55 chain of the human IL-2 receptor, said immunoglobulin having two pairs of heavy and light chains wherein:

each light chain comprises a complete human kappa chain constant region sequence and a variable region sequence;

##STR3## and each heavy chain comprises a complete human γ

chain constant region sequence and a variable region sequence;

##STR4##