Antibody Therapy

• US 20090092598A1
• Filed: 10/31/2007
• Published: 04/09/2009
• Est. Priority Date: 10/08/2002
• Status: Active Grant

• Current Assignee: Immunomedics, Inc.
• Original Assignee: Immunomedics, Inc.
• Inventors: Goldenberg, David M., Hansen, Hans J.
• Granted Patent: US 7,662,378 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 38/164 from bacteria
• CPC Class Codes: A61K 38/168 from plants
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/191 Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/196 Thrombopoietin
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 39/39558 : against tumor tissues, cells, antigens
• CPC Class Codes: A61K 51/1045 : against animal or human tumor cells or tumor cell determinants
• CPC Class Codes: A61K 51/1048 : the tumor cell determinant being a carcino embryonic antigen
• CPC Class Codes: A61K 51/1096 : radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: C07K 16/3007 : Carcino-embryonic Antigens
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

The present invention provides a composition comprising naked humanized, chimeric, and human anti-CEA antibodies and a therapeutic agent, which is useful for treatment of CEA expressing cancers and other diseases, and methods of use in treatment using this composition.

Claims

1. A naked, chimeric, humanized or human anti-carcinoembryonic antigen (anti-CEA) monoclonal antibody (MAb) wherein:

(i) the naked anti-CEA MAb is unreactive with human granulocytes;

(ii) the naked anti-CEA MAb has human IgG1 hinge and constant regions; and

(iii) administration of the naked anti-CEA MAb to a cancer that expresses CEA antigen sensitizes the cancer to the subsequent administration of a cancer therapeutic agent.

2. The naked anti-CEA antibody of claim 1, wherein the therapeutic agent is a second naked antibody, a cytotoxic agent, a drug, a radionuclide, an immunomodulator, a photoactive therapeutic agent, an immunoconjugate, a hormone, or a combination thereof.

3. The naked anti-CEA antibody of claim 2, wherein said combination thereof comprises vincristine, doxorubicin, DTIC and cyclophosphamide.

4. The naked anti-CEA antibody of claim 2, wherein said therapeutic agent is a second naked antibody or an immunoconjugate.

5. The naked anti-CEA antibody of claim 4, wherein said second naked antibody or immunoconjugate comprises a humanized, chimeric, human or murine antibody or fragment thereof reactive with EGP-1, EGP-2 (e.g., 17-1A), MUC-1, MUC-2, MUC-3, MUC-4, PAM-4, KC4, TAG-72, EGFR, EGP-b 2, HER2/neu, BrE3, Le-Y, A3, A33, Ep-CAM, AFP, Tn, Thomson-Friedenreich antigens, tumor necrosis antigens, VEGF or other tumor angiogenesis antigens, Ga 733, tenascin or fibronectin.

6. The naked anti-CEA antibody of claim 1, wherein said naked anti-CEA MAb is a naked humanized MN-14 antibody comprising the light chain variable region complementarity determining region (CDR) sequences CDR1 (KASQDVGTSVA, SEQ ID NO:

20);

CDR2 (WTSTRHT, SEQ ID NO;

     21); and

CDR3 (QQYSLYRS, SEQ ID NO;

     22); and

the heavy chain variable region CDRs CDR1 (TYWMS, SEQ ID NO;

     23);

CDR2 (EIHPDSSTINYAPSLKD, SEQ ID NO;

     24); and

CDR3 (LYFGFPWFAY, SEQ ID NO;

     25).

7. The naked anti-CEA antibody of claim 6, wherein the framework regions (FRs) of the light and heavy chain variable regions of said naked humanized MN-14 antibody comprise at least one amino acid substituted from corresponding FRs of a murine MN-14 monoclonal antibody.

8. The naked anti-CEA antibody of claim 1, wherein the cancer is medullary thyroid carcinoma or colon cancer.

9. The naked anti-CEA antibody of claim 2, wherein the cytotoxic agent is a drug or toxin.

10. The naked anti-CEA antibody of claim 9, wherein the drug possesses the pharmaceutical property selected from the group consisting of antimitotic, alkylating, antimetabolite, antiangiogenic, apoptotic, alkaloid, COX-2, and antibiotic agents and combinations thereof.

11. The naked anti-CEA antibody of claim 9, wherein the drug is selected from the group consisting of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, anthracyclines, taxanes, COX-2 inhibitors, pyrimidine analogs, purine analogs, antimetabolites, antibiotics, enzymes, epipodophyllotoxins, platinum coordination complexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, antagonists, endostatin, taxols, camptothecins, doxorubicins, and a combination thereof.

12. The naked anti-CEA antibody of claim 9, wherein the toxin is a microbial, plant or animal toxin selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtherin toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.

13. The naked anti-CEA antibody of claim 2, wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), a stem cell growth factor, erythropoietin, thrombopoietin and a combination thereof.

14. The naked anti-CEA antibody of claim 2, wherein the immunomodulator comprises IL-1, IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, interferon-γ

, TNF-α

or a combination thereof.

15. The naked anti-CEA antibody of claim 1, wherein combination of naked anti-CEA antibody and therapeutic agent is more effective for therapy of a CEA-expressing cancer than either antibody or therapeutic agent alone or the sum of the effects of naked anti-CEA antibody and therapeutic agent.

16. The naked anti-CEA antibody of claim 2, wherein the radionuclide is selected from the group consisting of ¹²⁵I, ¹³¹I, ⁹⁰Y, ⁸⁸Y, ²²⁵Ac, ¹⁷⁷Lu, ¹⁸⁸Re, ¹⁸⁶Re, and combinations thereof.

17. A method for treating human medullary thyroid carcinoma comprising administering to a human subject a naked anti-CEA antibody according to claim 1, wherein the combination of naked anti-CEA MAb and therapeutic agent is more effective for treatment of human medullary thyroid carcinoma than either naked anti-CEA MAb or therapeutic agent alone or the sum of the effects of naked anti-CEA MAb and therapeutic agent administered individually.

18. The method of claim 17, wherein said naked anti-CEA MAb is a naked humanized MN-14 antibody comprising the complementarity-determining regions (CDRs) of a murine MN-14 monoclonal antibody, wherein the naked anti-CEA MAb comprises the CDRs of the light chain variable region of said MN-14 antibody comprising CDR1 (KASQDVGTSVA, SEQ ID NO:

20);

CDR2 (WTSTRHT, SEQ ID NO;

     21); and

CDR3 (QQYSLYRS, SEQ ID NO;

     22); and

the CDRs of the heavy chain variable region of said MN-14 antibody comprising CDR1 (TYWMS, SEQ ID NO;

     23);

CDR2 (EIHPDSSTINYAPSLKD, SEQ ID NO;

     24); and

CDR3 (LYFGFPWFAY, SEQ ID NO;

     25).

19. The method of claim 18, wherein the framework regions (FRs) of the light and heavy chain variable regions of said naked humanized MN-14 antibody comprise at least one amino acid substituted from the corresponding FRs of a murine MN-14 monoclonal antibody.

20. The method of claim 19, wherein said naked humanized MN-14 antibody comprises at least one amino acid from said corresponding FR of said murine MN-14 light chain or heavy chain variable region.

21. A method for treating human colon cancer comprising administering to a subject a antibody according to claim 1, wherein the combination of naked anti-CEA MAb and therapeutic agent is more effective for treatment of human colon cancer than either naked anti-CEA MAb or therapeutic agent alone or the sum of the effects of naked anti-CEA MAb and therapeutic agent administered individually.

22. The method of claim 21, wherein said naked anti-CEA MAb is a naked humanized MN-14 antibody comprising the complementarity-determining regions (CDRs) of a murine MN-14 monoclonal antibody, wherein the naked anti-CEA MAb comprises the CDRs of the light chain variable region of said MN-14 antibody comprising CDR1 (KASQDVGTSVA, SEQ ID NO:

20);

CDR2 (WTSTRHT, SEQ ID NO;

     21); and

CDR3 (QQYSLYRS, SEQ ID NO;

     22); and

the CDRs of the heavy chain variable region of said MN-14 antibody comprising CDR1 (TYWMS, SEQ ID NO;

     23);

CDR2 (EIHPDSSTINYAPSLKD, SEQ ID NO;

     24); and

CDR3 (LYFGFPWFAY, SEQ ID NO;

     25).

23. The method of claim 22, wherein the framework regions (FRs) of the light and heavy chain variable regions of said naked humanized MN-14 antibody comprise at least one amino acid substituted from the corresponding FRs of a murine MN-14 monoclonal antibody.

24. The method of claim 23, wherein said naked humanized MN-14 antibody comprises at least one amino acid from said corresponding FR of said murine MN-14 light chain or heavy chain variable region.

25. A method of treating a CEA-expressing cancer comprising:

a) first administering to a subject with a CEA-expressing cancer a naked anti-CEA antibody according to claim 1;

b) second administering to the subject a cancer therapeutic agent, wherein administering the anti-CEA antibody to the subject sensitizes the cancer to the subsequent administration of the cancer therapeutic agent.