CD3-binding molecules capable of binding to human and non-human CD3

• US 9,587,021 B2
• Filed: 05/16/2012
• Issued: 03/07/2017
• Est. Priority Date: 05/21/2011
• Status: Active Grant

• Current Assignee: MacroGenics, Inc.
• Original Assignee: MacroGenics, Inc.
• Inventors: Huang, Ling, Johnson, Leslie S.
• Primary Examiner(s): SKELDING, ZACHARY S
• Application Number:
  US14/118,523
• Publication Number:
  US 20140099318A1
• Time in Patent Office: 1,756 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: C03C 17/38 : at least one coating being a coating of an organic material
• CPC Class Codes: C03C 17/42 : at least one coating of an organic material and at least one non-metal coating
• CPC Class Codes: C03C 2217/445 : Organic continuous phases
• CPC Class Codes: C03C 2217/465 : having a specific shape
• CPC Class Codes: C03C 2217/479 : Metals
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/32 : against translation products of oncogenes
• 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 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G02B 5/0808 : having a single reflecting layer G02B5/0883, G02B5/0891 take precedence
• CPC Class Codes: H01L 31/0547 : comprising light concentrating means of the reflecting type, e.g. parabolic mirrors, concentrators using total internal reflection
• CPC Class Codes: Y02E 10/52 : PV systems with concentrators

Abstract

CD3-binding molecules capable of binding to human and non-human CD3, and in particular to such molecules that are cross-reactive with CD3 of a non-human mammal (e.g., a cynomolgus monkey) are presented. Uses of such antibodies and antigen-binding fragments in the treatment of cancer, autoimmune and/or inflammatory diseases and other conditions are presented.

Claims

1. A CD3-binding molecule comprising an antigen-binding fragment of an antibody, wherein said antigen-binding fragment comprises an antibody CD3-specific VL domain and an antibody CD3-specific VH domain, wherein said CD3-specific VL domain and said CD3-specific VH domain form an antigen-binding domain capable of immunospecifically binding to both an epitope of human CD3 and to an epitope of the CD3 of a non-human mammal, wherein:

(I) said CD3-specific VL domain is selected from the group consisting of h mab2 VL-4 (SEQ ID NO;

22), h mab2 VL-6 (SEQ ID NO;

26), h-mab2 VL-7 (SEQ ID NO;

28), h-mab2 VL-8 (SEQ ID NO;

30), h-mab2 VL-9 (SEQ ID NO;

32), and h-mab2 VL-10 (SEQ ID NO;

34), and

(II) said CD3-specific VH domain is selected from the group consisting of h-mab2 VH-1 (SEQ ID NO;

36), h-mab2 VH-2 (SEQ ID NO;

38), h-mab2 VH-3 (SEQ ID NO;

40), h-mab2 VH-4 (SEQ ID NO;

42), h-mab2 VH-5 (SEQ ID NO;

44), h-mab2 VH-6 (SEQ ID NO;

46), h-mab2 VH-7 (SEQ ID NO;

48), and h-mab2 VH-8 (SEQ ID NO;

50).

2. The CD3-binding molecule of claim 1, wherein said CD3-specific VL domain is h-mab2 VL-6 (SEQ ID NO:

26).

3. The CD3-binding molecule of claim 1, wherein said CD3-specific VH domain is h-mab2 VH-8 (SEQ ID NO:

50), or h-mab2 VH-4 (SEQ ID NO;

42).

4. The CD3-binding molecule of claim 1, wherein said molecule is an antibody.

5. The CD3-binding molecule of claim 4, wherein said antibody:

(A) lacks an Fc region;

or

(B) comprises an Fc region that;

(i) lacks effector function;

or

(ii) has reduced effector function;

or

(iii) impairs the ability of the Fc region of said antibody to bind to an Fc receptor;

wherein said lack of effector function, said reduction in effector function and said impairment of binding ability is relative to that of a wild-type Fc receptor.

6. The CD3-binding molecule of claim 1, wherein said molecule is a CD3-binding diabody that comprises a first polypeptide chain and a second polypeptide chain, said chains being covalently bonded to one another, wherein:

(I) said first polypeptide chain comprises an amino terminus and a carboxy terminus and from N-terminus to C-terminus;

(i) a domain (A) comprising said CD3-specific VL domain;

(ii) a domain (B) comprising a binding region of a heavy chain variable domain of a second immunoglobulin (VH2); and

(iii) a domain (C);

wherein said domains (A) and (B) do not associate with one another to form an epitope binding site;

and

(II) said second polypeptide chain comprises an amino terminus and a carboxy terminus and from N-terminus to C-terminus;

(i) a domain (D) comprising a binding region of a light chain variable domain of said second immunoglobulin (VL2);

(ii) a domain (E) comprising said CD3-specific VH domain;

and

(iii) a domain (F);

wherein said domains (D) and (E) do not associate with one another to form an epitope binding site; and

wherein;

(1) said domains (A) and (E) associate to form said antigen-binding domain that is capable of immunospecifically binding to both human CD3 and to the CD3 of a non-human mammal;

(2) said domains (B) and (D) associate to form a binding site that immunospecifically binds to a second epitope, said second epitope being different from the CD3 epitope bound by the antigen-binding domain formed from said association of said domains (A) and (E); and

(3) said domains (C) and (F) are covalently associated together.

7. The CD3-binding molecule of claim 6, wherein said second epitope is not an epitope of CD3.

8. The CD3-binding molecule of claim 6, wherein said second epitope is an epitope of CD3 that is different from the CD3 epitope bound by the antigen-binding domain formed from said association of said domains (A) and (E).

9. The CD3-binding molecule of claim 1, which is humanized.

10. The CD3-binding molecule of claim 1, which is capable of immunospecifically binding to CD3 and to fluorescein.

11. The CD3-binding molecule of claim 1, which is capable of immunospecifically binding to both:

(i) CD3; and

(ii) (a) a tumor antigen, or

(b) a cell surface antigen, receptor or receptor ligand.

12. The CD3-binding molecule of claim 11, wherein said molecule is capable of immunospecifically binding to CD3 and to a tumor antigen expressed on a tumor cell, wherein said tumor cell is a tumor cell from a cancer selected from the group consisting of:

breast cancer, prostate cancer, gastric cancer, lung cancer, stomach cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, ovarian cancer, oral cavity cancer, pharyngeal cancer, esophageal cancer, laryngeal cancer, bone cancer, skin cancer, melanoma, uterine cancer, testicular cancer, bladder cancer, kidney cancer, brain cancer, glioblastoma, thyroid cancer, lymphoma, myeloma, and leukemia.

13. The CD3-binding molecule of claim 11, wherein said molecule is capable of immunospecifically binding to CD3 and to a cell surface antigen, receptor or receptor ligand, wherein said cell surface antigen, receptor or receptor ligand is HER2/neu, B7-H3, CD20, PSMA, IGF-1R, or Ep-CAM.

14. The CD3-binding molecule of claim 11, wherein said molecule is capable of immunospecifically binding to CD3 and to a cell surface antigen, receptor or receptor ligand, wherein said cell surface antigen, receptor or receptor ligand is a molecule involved in a T cell-B cell association, wherein said molecule involved in said T cell-B cell association is selected from the group consisting of CD19, CD20, CD22, CD23, CD27, CD32B, CD38, CD40, CD79a, CD79b, CD80, CD86, LFA-I, LFA-3 and CFA-I.

15. A pharmaceutical composition comprising the CD3-binding molecule of claim 1, and a pharmaceutically acceptable carrier, excipient or diluent.

16. A method for treating cancer characterized by a cancer antigen comprising administering an effective amount of a pharmaceutical composition comprising the CD3-binding molecule of claim 11 and a pharmaceutically acceptable carrier, excipient or diluent, wherein said CD3-binding molecule is capable of binding to both CD3 and said cancer antigen.

17. The CD3-binding molecule of claim 6, wherein:

(A) said domain (B) comprises amino acid residues 119-238 of SEQ ID NO;

65; and

(B) said domain (D) comprises amino acid residues 1-107 of SEQ ID NO;

64.

18. The CD3-binding molecule of claim 6, wherein:

(A) said domain (B) comprises amino acid residues 119-240 of SEQ ID NO;

67; and

(B) said domain (D) comprises amino acid residues 1-107 of SEQ ID NO;

66.

19. The CD3-binding molecule of claim 6, wherein said CD3-specific VL domain is h-mab2 VL-6 (SEQ ID NO:

26).

20. The CD3-binding molecule of claim 6, wherein said CD3-specific VH domain is h-mab2 VH-8 (SEQ ID NO:

50) or h-mab2 VH-4 (SEQ ID NO;

42).

21. The CD3-binding molecule of claim 20, wherein:

(A) said CD3-specific VL domain is h-mab2 VL-6 (SEQ ID NO;

26); and

(B) said CD3-specific VH domain is h-mab2 VH-4 (SEQ ID NO;

42).

22. The CD3-binding molecule of claim 6, wherein said CD3-binding diabody comprises an Fc domain or portion thereof.

23. The CD3-binding molecule of claim 22, wherein:

(A) said first polypeptide chain additionally comprises an E coil sequence and said second polypeptide chain additionally comprises a K coil sequence;

or

(B) said first polypeptide chain additionally comprises a K coil sequence and said second polypeptide chain additionally comprises an E coil sequence;

wherein said E coil sequence is amino acid residues 244-271 of SEQ ID NO;

62, and said K coil sequence is residues 247-274 of SEQ ID NO;

63.

24. The CD3-binding molecule of claim 6, wherein:

(A) said first polypeptide chain additionally comprises an E coil sequence and said second polypeptide chain additionally comprises a K coil sequence;

or

(B) said first polypeptide chain additionally comprises a K coil sequence and said second polypeptide chain additionally comprises an E coil sequence;

wherein said E coil sequence is amino acid residues 244-271 of SEQ ID NO;

62, and said K coil sequence is residues 247-274 of SEQ ID NO;

63.