TAG-72 specific CH2 domain deleted antibodies

• US 7,319,139 B2
• Filed: 01/29/2002
• Issued: 01/15/2008
• Est. Priority Date: 01/29/2001
• Status: Expired due to Term

• Current Assignee: Biogen, Inc.
• Original Assignee: Biogen, Inc.
• Inventors: Braslawsky, Gary R, Chinn, Paul, Hanna, Nabil, Hariharan, Kandasamy
• Primary Examiner(s): Blanchard; David J.
• Application Number:
  US10/058,069
• Publication Number:
  US 20070280881A1
• Time in Patent Office: 2,177 Days
• Field of Search: 424/130.1, 424/133.1, 424/135.1, 424/136.1, 424/143.1, 424/155.1, 424/156.1, 424/181.1, 424/183.1, 530/391.3, 530/391.7, 530/387.1, 530/387.3, 530/387.7, 530/388.8
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6869 the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
• CPC Class Codes: A61K 47/6901 Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
• CPC Class Codes: A61K 51/1027 against receptors, cell-surface antigens or cell-surface determinants
• CPC Class Codes: A61K 51/1045 against animal or human tumor cells or tumor cell determinants
• CPC Class Codes: A61K 51/1072 the tumor cell being from the reproductive system, e.g. ovaria, uterus, testes or prostate
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/3069 Reproductive system, e.g. ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C12N 15/85 for animal cells
• CPC Class Codes: C12P 21/02 having a known sequence of two or more amino acids, e.g. glutathione

Abstract

Methods, compositions and kits comprising dimeric antibodies for the treatment of neoplastic, autoimmune or other disorders are provided. The dimeric antibodies of the instant invention may comprise two antibody molecules (H₄L₄) having the same antigen binding specificity (homodimers) or, alternatively, may comprise two different antibody molecules having binding specificity for two distinct antigens (heterodimers). In preferred embodiments the antibody molecules comprising the dimers are non-covalently associated.

Claims

1. A kit useful for the treatment of a mammal suffering from or predisposed to a neoplastic disorder comprising at least one container containing substantially purified dimeric antibodies that bind specifically to TAG-72,

each dimeric antibody comprising two antibodies that are non-covalently associated to form a tetravalent antibody dimer having four antigen-biding sites that bind specifically to TAG-72,

wherein each of the antibodies in the dimer comprises two antibody heavy chain polypeptides having the heavy chain variable region amino acid sequence shown in FIG. 4A (SEQ ID NO:

7), and two antibody light chain polypeptides having the light chain variable region amino acid sequence shown in FIG. 5A (SEQ ID NO;

     9), and has two antigen-binding sites that bind specifically to TAG-72;

wherein each of the four antibody heavy chain polypeptides in the dimeric antibody comprises a human gamma-1 constant region wherein a C_H2 domain is deleted from, and a C_H3 domain is fused directly to the hinge region;

wherein the dimeric tetravalent antibodies are purified to greater than 98% homogeneity;

and further comprising a label or an insert indicating that said dimeric antibody may be used to treat said neoplastic disorder.

6. The kit of claim 1, wherein said antibody dimer comprises four antibody heavy chain polypeptides having the heavy chain polypeptide amino acid sequence shown in FIG. 4A (SEQ ID NO:

7), and four antibody light chain polypeptides having the light chain polypeptide amino acid sequence shown in FIG. 5A (SEQ ID NO;

     9).

7. The kit of claim 1 wherein said neoplastic disorder is colon cancer.

2. Substantially purified dimeric antibodies that bind specifically to TAG-72,

each dimeric antibody comprising two antibodies that are non-covalently associated to form a tetravalent antibody dimer having four antigen-binding sites that bind specifically to TAG-72,

wherein each of the antibodies in the dimer comprises two antibody heavy chain polypeptides having the heavy chain variable region amino acid sequence shown in FIG. 4A (SEQ ID NO:

7), and two antibody light chain polypeptides having the light chain variable region amino acid sequence shown in FIG. 5A (SEQ ID NO;

     9), and has two antigen-binding sites that bind specifically to TAG-72; and

wherein each of the four antibody heavy chain polypeptides in the dimeric antibody comprises a human gamma-1 constant region wherein a C_H2 domain is deleted from, and a C_H3 domain is fused directly to the hinge region;

wherein the dimeric tetravalent antibodies are purified to greater than 98% homogeneity.

3. The substantially purified dimeric antibodies of claim 2, wherein said dimeric antibody is conjugated to a cytotoxic agent.

4. The substantially purified dimeric antibodies of claim 3, wherein said cytotoxic agent comprises a radioisotope.

5. The substantially purified dimeric antibodies of claim 4, wherein said radioisotope is selected from the group consisting of ⁹⁰Y, ¹²⁵I, ¹³¹I, ¹²³I, ¹¹¹In, ¹⁰⁵Rh, ¹⁵³Sm, ⁶⁷Cu, ⁶⁷Ga, ¹⁶⁶Ho, 177Lu, ¹⁸⁶Re and ¹⁸⁸Re.

8. The substantially purified dimeric antibodies of claim 2, wherein said antibody dimer comprises four antibody heavy chain polypeptides having the heavy chain polypeptide amino acid sequence shown in FIG. 4A (SEQ ID NO:

7), and four antibody light chain polypeptides having the light chain polypeptide amino acid sequence shown in FIG. 5A (SEQ ID NO;

     9).

9. The substantially purified dimeric antibodies of claim 3, wherein said cytotoxic agent is selected from the group consisting of cytostatic agents, alkylating agents, antimetabolites, anti-proliferative agents, tubulin binding agents, hormones and hormone antagonists, anthracycline drugs, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, pteridine drugs, diynenes, podophyllotoxins, toxic enzymes, and radiosensitizing drugs.

10. The substantially purified dimeric antibodies of claim 9, wherein said cytotoxic agent is selected from the group consisting of mechlorethamine, triethylenephosphoramide, cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, triaziquone, nitrosourea compounds, adriamycin, carminomycin, daunorubicin (daunomycin), doxorubicin, aminopterin, methotrexate, methopterin, mithramycin, streptonigrin, dichloromethotrexate, mitomycin C, actinomycin-D, porfiromycin, 5-fluorouracil, floxuridine, ftorafur, 6-mercaptopurine, cytarabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, taxol, taxane, cytochalasin B, gramicidin D, ethidium bromide, emetine, tenoposide, colchicin, dihydroxy anthracin dione, mitoxantrone, procaine, tetracaine, lidocaine, propranolol, puromycin, ricin subunit A, abrin, diptheria toxin, botulinum, cyanginosins, saxitoxin, shigatoxin, tetanus, tetrodotoxin, trichothecene, verrucologen, corticosteroids, progestins, estrogens, antiestrogens, androgens, aromatase inhibitors, calicheamicin, esperamicins, and dynemicins.

11. The substantially purified dimeric antibodies of claim 9, wherein said hormone or hormone antgonist is selected from the group consisting of prednisone, hydroxyprogesterone, medroprogesterone, diethylstilbestrol, tamoxifen, testosterone, and aminogluthetimide.

12. The substantially purified dimeric antibodies of claim 3, wherein said cytotoxic agent is a prodrug selected from the group consisting of phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate containing prodrugs, peptide containing prodrugs, (-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs, optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosinem, and 5-fluorouridine prodrugs that can be converted to the more active cytotoxic free drug.

13. A kit useful for the treatment of a mammal suffering from or predisposed to a neoplastic disorder comprising at least one container containing substantially purified dimeric antibodies that bind specifically to TAG-72,

each dimeric antibody comprising two antibodies that are non-covalently associated to form a tetravalent antibody dimer having four antigen-binding sites that bind specifically to TAG-72,

wherein each of the antibodies in the dimer comprises two antibody heavy chain polypeptides having the heavy chain polypeptide amino acid sequence shown in FIG. 4A (SEQ ID NO:

7) comprising a human gamma-1 constant region wherein the C_H2 domain is deleted and the C_H3 domain is fused directly to the hinge region, and two antibody light chain polypeptides having the light chain polypeptide amino acid sequence shown in FIG. 5A (SEQ ID NO;

     9), and has two antigen-binding sites that bind specifically to TAG-72;

wherein the dimeric tetravalent antibodies are purified to greater than 98% homogeneity;

and further comprising a label or in insert indicating that said dimeric antibody may be used to treat said neoplastic disorder.

14. The kit of claim 13 wherein said neoplastic disorder is colon cancer.

15. Substantially purified dimeric antibodies that bind specifically to TAG-72,

each dimeric antibody comprising two antibodies that are non-covalently associated to form a tetravalent antibody dimer having four antigen-binding sites that bind specifically to TAG-72,

wherein each of the antibodies in the dimer comprises two antibody heavy chain polypeptides having the heavy chain polypeptide amino acid sequence shown in FIG. 4A (SEQ ID NO:

7) comprising a human gamma-1 constant region wherein the C_H2 domain is deleted and the C_H3 domain is fused directly to the hinge region, and two antibody light chain polypeptides having the light chain polypeptide amino acid sequence shown in FIG. 5A (SEQ ID NO;

     9), and has two antigen-binding sites that bind specifically to TAG-72;

wherein the dimeric tetravalent antibodies are purified to greater than 98% homogeneity.

16. The substantially purified dimeric antibodies of claim 15, wherein said dimeric antibody is conjugated to a cytotoxic agent.

17. The substantially purified dimeric antibodies of claim 15, wherein said cytotoxic agent comprises a radioisotope.

18. The substantially purified dimeric antibodies of claim 15, wherein said radioisotope is selected from the group consisting of ⁹⁰Y, ¹²⁵I, ¹³¹I, ¹²³I, ¹¹¹In, ¹⁰⁵Rh, ¹⁵³Sm, ⁶⁷Cu, ⁶⁷Ga, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁸⁶Re and ¹⁸⁸Re.

19. The substantially purified dimeric antibodies of claim 16, wherein said cytotoxic agent is selected from the group consisting of cytostatic agents, alkylating agents, antimetabolites, anti-proliferative agents, tubulin binding agents, hormones and hormone antagonists, anthracycline drugs, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, pteridine drugs, diynenes, podophyllotoxins, toxic enzymes, and radiosensitizing drugs.

20. The substantially purified dimeric antibodies of claim 19, wherein said cytotoxic agent is selected from the group consisting of mechlorethamine, triethylenephosphoramide, cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, triaziquone, nitrosourea compounds, adriamycin, carminomycin, daunorubicin (daunomycin), doxorubicin, aminopterin, methotrexate, methopterin, mithramycin, streptonigrin, dichloromethotrexate, mitomycin C, atinomycin-D, porfiromycin, 5-fluorouracil, floxuridine, ftorafur, 6-mercaptopurine, cytarabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, taxol, taxane, cytochalasin B, gramicidin D, ethidium bromide, emetine, tenoposide, colchicin, dihydroxy anthracin dione, mitoxantrone, procaine, tetracaine, lidocaine, propranolol, puromycin, ricin subunit A, abrin, diptheria toxin, botulinum, cyanginosins, saxitoxin, shigatoxin, tetanus, tetrodotoxin, trichothecene, verrucologen, corticosteroids, progestins, estrogens, antiestrogens, androgens, aromatase inhibitors, calichcamicin, esperamicins, and dynemicins.

21. The substantially purified dimeric antibodies of claim 19, wherein said hormone or hormone antagonist is selected from the group consisting of prednisone, hydroxyprogesterone, medroprogesterone, diethylstilbestrol, tamoxifen, testosterone, and aminogluthetimide.

22. The substantially purified dimeric antibodies of claim 16, wherein said cytotoxic agent is a prodrug selected from the group consisting of phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate containing prodrugs, peptide containing prodrugs, (-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs, optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosinem, and 5-fluorouridine prodrugs that can be converted to the more active cytotoxic free drug.