M-csf specific monoclonal antibody and uses thereof

a monoclonal antibody and specific technology, applied in the field of mcsf specific monoclonal antibody, can solve the problems of high susceptibility, serious morbidity, and substantial refractory to cancer metastasis therapy, and achieve the effect of preventing or reducing bone loss

Inactive Publication Date: 2009-12-31
XOMA TECH LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]In yet another embodiment, the antibody comprises a constant region and one or more heavy and light chain variable framework regions of a human antibody sequence. In a related embodiment, the antibody comprises a modified or unmodified constant region of a human IgG1, IgG2, IgG3 or IgG4. In a preferred embodiment, the constant region is human IgG1 or IgG4, which may optionally be modified to enhance or decrease certain properties. In the case of IgG1, modifications to the constant region, particularly the hinge or CH2 region, may increase or decrease effector function, including ADCC and / or CDC activity. In other embodiments, an IgG2 constant region is modified to decrease antibody-antigen aggregate formation. In the case of IgG4, modifications to the constant region, particularly the hinge region, may reduce the formation of half-antibodies.
[0032]Antibodies of the present invention are contemplated to have numerous desirable characteristics for the treatment of diseases and disorders. In one embodiment of the invention, the any one of aforementioned antibodies that binds to M-CSF for preventing a subject afflicted with a disease that causes or contributes to osteolysis, wherein the antibody effectively reduces the severity of bone loss associated with the disease, is provided. Similarly, any one of aforementioned antibodies that binds to M-CSF is provided for treating a subject afflicted with a disease that causes or contributes to osteolysis, wherein said antibody effectively reduces the severity of bone loss associated with the disease.
[0043]In still another embodiment of the invention, a method of preventing or reducing bone loss is provided comprising administering to a subject afflicted with a disease that causes or contributes to osteolysis a therapeutically effective amount of any one of the aforementioned antibodies, thereby preventing or reducing bone loss associated with the disease. In a related embodiment, a method of treating a subject afflicted with a disease that causes or contributes to osteolysis is provided comprising administering to said subject a therapeutically effective amount of the antibody of any one of the aforementioned antibodies, thereby reducing the severity of bone loss associated with the disease.
[0058]Kits are also contemplated by the present invention. In one embodiment, a kit comprising a therapeutically effective amount of an antibody of the invention, packaged in a container, such as a vial or bottle, and further comprising a label attached to or packaged with the container, the label describing the contents of the container and providing indications and / or instructions regarding use of the contents of the container to prevent or reduce bone loss is provided.

Problems solved by technology

Despite intensive efforts to develop treatments, cancer metastasis remains substantially refractory to therapy.
The occurrence of osteolytic bone metastases causes serious morbidity due to intractable pain, high susceptibility to fracture, nerve compression and hypercalcemia.
Despite the importance of these clinical problems, there are few available treatments for bone loss associated with cancer metastasis.

Method used

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  • M-csf specific monoclonal antibody and uses thereof
  • M-csf specific monoclonal antibody and uses thereof
  • M-csf specific monoclonal antibody and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0422]This example shows that M-CSF antibodies RX1 and 5A1 are species specific and that antibodies RX1, MC1, and MC3 neutralize human M-CSF activity. RX1 is a commercially sold antibody that was available more than a year prior to the filing date of this application. Exemplary commercial sources include, but are not limited to, mouse anti-human M-CSF monoclonal antibody clones 116, 692, and 21 (Anogen); anti-human M-CSF antibody clones 21113.131, 26730, and 26786 (R & D Systems, Inc.); and anti-human M-CSF antibodyclone M16 (Antigenix America, Inc.).

[0423]To test the neutralizing activity of RX1 and 5A1, a proliferation assay of M-NFS-60 cell line was used (American Type Culture Collection Accession No. CRL-1838, available from ATCC in Rockville, Md., USA, derived from a myelogenous leukemia induced with the Cas-Br-MuLV wild mouse ecotropic retrovirous, responsive to both interleukin 3 and M-CSF and which contain a truncated c-myb proto-oncogene caused by the integration of a retro...

example 2

[0425]This example shows that antibody RX1 effectively inhibits osteolysis in a human xenograft model at a dose of 5 mg / kg. Female nude mice at the age of 4-7 weeks old, average weight ˜20 g were used in this study. Tumor cells (MDA-MB-23 1, 3×105) suspended in 10 μl of saline was be injected into the right tibia bone marrow cavity. Radiograms of the hind legs were taken one day after tumor inoculation for getting baseline image and checking for bone fracture caused by injection. Mice were randomized into treatment groups at 10 mice per group including PBS and RX1 at 5 mg / kg, injected i.p. once a week for 6 weeks. At the end of study, radiograms of the hind legs were taken again and compared against baseline for bone damage. The degree of bone damage caused by tumor was defined as shown in FIG. 6. The group with RX1 5 mg / kg treatment showed statistically significant protection of the bone from tumor-cased damage.

example 3

[0426]This example shows that the number of metastases is reduced when antibody RX1 is administered to human breast cancer MDA-MB-231 bearing nude mice at a concentration of 5 mg / kg.

[0427]Female nude mice at the age of 4-7 weeks old, average weight ˜20 g were used for this study. Tumor cells (MDA-MB-231, 3×105) suspended in 10 μl of saline was injected into the right tibia bone marrow cavity. Radiograms of the hind legs were taken one day after tumor inoculation for getting baseline image and checking for bone fracture caused by injection. Mice were randomly grouped into the treatment groups including PBS and RX1 at mg / kg injected i.p. once a week for 6 weeks. At the end of study, lungs of each treatment group were collected and fixed in Bouin's solution for metastatic lung nodule counting.

[0428]As shown in FIG. 7, that the number of metastases is reduced when antibody RX1 is administered to human breast cancer MDA-MB-231 bearing nude mice at a dose of 5 mg / kg.

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Abstract

M-CSF-specific antibody RX1 is provided, along with pharmaceutical compositions containing antibody RX1, kits containing a pharmaceutical composition, and methods of preventing and treating bone loss in a subject afflicted with an osteolytic disease.

Description

[0001]This application claims priority of U.S. Provisional Application No. 60 / 535,181, filed Jan. 7, 2004, and U.S. Provisional Application No. 60 / 576,417 filed Jun. 2, 2004, each of which is incorporated by reference herein in its entirety.TECHNICAL FIELD[0002]This invention relates to methods for preventing and treating osteolysis, cancer metastasis and bone loss associated with cancer metastasis by administering an M-CSF-specific antibody to a subject.BACKGROUND OF THE INVENTION[0003]Cancer metastasis is the primary cause of post-operation or post-therapy recurrence in cancer patients. Despite intensive efforts to develop treatments, cancer metastasis remains substantially refractory to therapy. Bone is one of the most common sites of metastasis of various types of human cancers (e.g., breast, lung, prostate and thyroid cancers). The occurrence of osteolytic bone metastases causes serious morbidity due to intractable pain, high susceptibility to fracture, nerve compression and hy...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07K16/00A61P35/00A61P19/00C07K16/24
CPCA61K2039/505C07K16/243C07K2316/96C07K2317/21C07K2317/24A61K39/3955C07K2317/73C07K2317/92C07K2317/34A61K31/663C07K2317/55A61K31/675A61K39/39558A61K45/06C07K2317/51C07K2317/515C07K2317/52C07K2317/56C07K2317/565C07K2317/76
Inventor LIU, CHENGZIMMERMAN, DEBORAH LEEHARROWE, GREGORY M.KOTHS, KIRSTONKAVANAUGH, WILLIAM M.LONG, LIHORWITZ, ARNOLDCALDERON-CACIA, MARIA
Owner XOMA TECH LTD
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