Antibody induced cell membrane wounding

• US 9,458,241 B2
• Filed: 02/19/2013
• Issued: 10/04/2016
• Est. Priority Date: 11/05/2004
• Status: Active Grant

• Current Assignee: Mcure Biosciences Incorporated, Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: IGM Biosciences, Inc.
• Inventors: Bhat, Neelima M, Bieber, Marcia M., Teng, Nelson N. H., Sanders, Martin E.
• Primary Examiner(s): Reddig, Peter J
• Application Number:
  US13/770,619
• Publication Number:
  US 20130164283A1
• Time in Patent Office: 1,323 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• 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 38/50 acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man

Abstract

Compositions and methods for inducing cell membrane wounding, cell permeabilization and cell killing are provided. The composition comprises a polyvalent agent that binds to a highly expressed cell surface antigen present on the surface of a cell. Preferably, the cell surface antigen is associated with the cytoskeleton of the cell. A preferred polyvalent agent is an IgM, and enhanced cell wounding and killing can be provided by the addition of a crosslinking agent. At sublethal concentrations in vivo, the cell wounding antibodies permeabilize cells and dramatically enhance response to chemotherapeutic agents, even in patients refractory to the chemotherapeutic agents.

Claims

1. A method of treating a mammal suffering from a condition characterized by hyperproliferation of B cells, wherein said hyperproliferating B-cells are cancer cells, comprising administering a cell membrane-wounding VH4-34antibody that binds to the CDIM epitope on the surface of B cells, in combination with a second cytotoxic agent, wherein said cell membrane wounding VH4-34 antibody is administered at a dosage that was determined to cause membrane pores that allow the second agent to enter said hyperproliferating B-cells to synergistically reduce viability of said hyperproliferating B cells, wherein the VH4-34 antibody is an IgM.

2. A method of treating a mammal suffering from a condition characterized by hyperproliferation of B cells, wherein said hyperproliferating B-cells are cancer cells, comprising administering a cell membrane-wounding VH4-34antibody that binds to the CDIM epitope on the surface of B cells, in combination with a second agent, wherein said cell membrane wounding VH4-34 antibody is administered at a dosage that was determined to cause membrane pores that allow the second agent to enter said hyperproliferating B-cells to synergistically reduce viability of said hyperproliferating B cells, wherein said second agent is a cytotoxic agent that interferes with the polymerization or depolymerization of microtubules.

3. The method of claim 2, wherein the cytotoxic agent that interferes with the polymerization or depolymerization of microtubules is a taxane, vinca alkaloid or colchicine, or mixtures thereof.

4. The method of claim 3, wherein the vinca alkaloid is vinblastine, vincristine, vindesine, or vinorelbine, or mixtures thereof.

5. The method of claim 4, wherein the taxane is paclitaxel, or docetaxel, or mixtures thereof.

9. The method of claim 2, wherein the condition characterized by a hyperproliferation of B cells is lymphoid cancer.

10. The method of claim 9, wherein the lymphoid cancer is acute or chronic leukemia, or lymphoma, of B-cell origin.

11. The method of claim 10, wherein the lymphoid cancer is acute lymphocytic leukemia (ALL), non-Hodgkins lymphoma (NHL), Burkitt'"'"'s lymphoma, B progenitor ALL, adult ALL, or chronic lymphocytic leukemia (CLL).

12. The method of claim 2, wherein the viability of hyperproliferating B cells is reduced to about 42 percent.

13. The method of claim 2, wherein the viability of hyperproliferating B cells is reduced to about 30 percent.

14. The method of claim 2, wherein said cell membrane wounding VH4-34 antibody is administered at a dosage of about 1.25 mg/kg bodyweight.

6. A method of treating a mammal suffering from a condition characterized by hyperproliferation of B cells, wherein said hyperproliferating B-cells are cancer cells, comprising administering a cell membrane-wounding VH4-34antibody that binds to the CDIM epitope on the surface of B cells, in combination with a second cytotoxic agent, wherein said cell membrane wounding VH4-34 antibody is administered at a dosage that was determined to cause membrane pores that allow the second agent to enter said hyperproliferating B-cells to synergistically reduce viability of said hyperproliferating B cells, wherein the second agent is a cytotoxic antibody.

7. The method of claim 6, wherein the antibody has specific binding for CD11a, CD19, CD20, CD21, CD22, CD25, CD34, CD37, CD38, CD40, CD45, CD52, CD80, CD 86, IL-4R, IL-6R, IL-8R, IL-13R, integrin (VLA4), BLYS receptor, cell surface idiotypic Ig, or mixtures thereof.

8. The method of claim 6, wherein the antibody is rituximab, or anti-CD52.

15. The method of claim 6, wherein the condition characterized by a hyperproliferation of B cells is lymphoid cancer.

16. The method of claim 15, wherein the lymphoid cancer is acute or chronic leukemia, or lymphoma, of B-cell origin.

17. The method of claim 16, wherein the lymphoid cancer is acute lymphocytic leukemia (ALL), non-Hodgkins lymphoma (NHL), Burkitt'"'"'s lymphoma, B progenitor ALL, adult ALL, or chronic lymphocytic leukemia (CLL).

18. The method of claim 6, wherein the viability of hyperproliferating B cells is reduced to about 42 percent.

19. The method of claim 6, wherein the viability of hyperproliferating B cells is reduced to about 30 percent.

20. The method of claim 6, wherein said cell membrane wounding VH4-34 antibody is administered at a dosage of about 1.25 mg/kg bodyweight.