Use of antibodies against the MUC18 antigen
The present invention relates generally to the generation and characterization of anti-MUC18 monoclonal antibodies. The invention further relates to the use of such anti-MUC18 antibodies in the diagnosis and treatment of disorders associated with increased activity of MUC18, in particular, tumors, such as melanomas.
1 . A human monoclonal antibody, or binding fragment thereof, that binds MUC18 with a Kd of less than 0.69 nM.
2 . The monoclonal antibody of claim 1 , wherein the antibody is mAb 3.19.1.
3 . A human monoclonal antibody, or binding fragment thereof, that binds MUC18, wherein the antibody, or binding fragment thereof, has one or more activity selected from:
(a) suppression of invasion of A375-SM and WM-2264 melanoma cells through matrigel-coated membrane in vitro;
(b) suppression of cell growth of WM-2264 tumor cells in vivo;
(c) suppression of formation of lung metastasis of melanoma A375-SM and WM-2264 cells in vivo; and
(d) prolongation of survival of mice bearing WM-2644 metastatic melanoma tumors in vivo.
4 . The monoclonal antibody, or binding fragment thereof, of claim 3 , wherein the concentration of antibody necessary to suppress cell growth of WM-2264 tumor cells in vivo is about 1 mg of antibody per week in a mouse model.
5 . The monoclonal antibody, or binding fragment thereof, of claim 4 , wherein the concentration of antibody necessary to suppress cell growth of WM-2264 tumor cells in vivo is about 100 μg of antibody per week in a mouse model.
6 . The monoclonal antibody of claim 3 , wherein the antibody is mAb 3.19.1.
7 . The monoclonal antibody, or binding fragment thereof, of claim 1 in association with a pharmaceutically acceptable carrier.
8 . A nucleic acid molecule encoding the monoclonal antibody, or binding fragment thereof, of claim 1 .
9 . A vector comprising the nucleic acid molecule of claim 8 .
10 . A host cell comprising the vector of claim 9 .
11 . A method of inhibiting tumor growth associated with the expression of the MUC18 tumor antigen in an animal, comprising:
selecting an animal in need of treatment for a tumor, wherein the tumor comprises cells expressing MUC18;
administering to said animal a therapeutically effective dose of the antibody, or binding fragment thereof, of claim 1 .
12 . The method of claim 11 , wherein said antibody is conjugated to a therapeutic or cytotoxic agent.
13 . The method of claim 12 , wherein the cytotoxic agent is ricin.
14 . The method of claim 12 , wherein the therapeutic agent is a radioisotope.
15 . The method of claim 11 , wherein said tumor is melanoma.
16 . The method of claim 11 , wherein said tumor is a lung tumor.
17 . The method of claim 11 , wherein said tumor growth is tumor metastasis.
18 . A method of inhibiting cell invasion associated with melanoma, comprising:
selecting an animal in need of treatment for melanoma;
administering to said animal a therapeutically effective dose of the antibody, or binding fragment thereof, of claim 1 .
19 . A method of increasing survival of an animal having a metastatic tumor that expresses MUC18, comprising:
selecting an animal in need of treatment for a metastatic tumor, wherein the tumor comprises cells expressing MUC18;
administering to said animal a therapeutically effective dose of the antibody, or binding fragment thereof, of claim 1.