ALPHA AND GAMMA-D POLYGLUTAMATED ANTIFOLATES AND USES THEREOF
The disclosure relates generally to polyglutamated antifolates, formulations containing liposomes filled with alpha or D-gamma polyglutamated antifolates, methods of making the polyglutamated antifolates and liposome containing formulations, and methods of using polyglutamated antifolates and liposome containing formulations to treat hyerproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., an autoimmune disease such as rheumatoid arthritis).
1 . A composition comprising an alpha or D-gamma polyglutamated polyglutamated antifolate.
2 . The composition of claim 1 wherein the polyglutamated antifolate comprises L-glutamates linked by their alpha carboxyl groups.
3 . The composition according to claim 1 , wherein composition comprises alpha or D-gamma pentaglutamated or hexaglutamated antifolate.
4 . The composition according to claim 3 , wherein the alpha or D-gamma polyglutamated antifolate is a member selected from the group consisting of: polyglutamated methotrexate (MTX), polyglutamated pemetrexed (PMX), polyglutamated lometrexol (LTX), polyglutamated AG2034, polyglutamated raltitrexed (RTX), polyglutamated piritrexim, polyglutamated pralatrexate, polyglutamated AG2034, polyglutamated GW1843, polyglutamated aminopterin, and polyglutamated LY309887.
5 . The composition according to claim 4 , wherein the alpha or D-gamma polyglutamated antifolate is polyglutamated PMX, MTX, RTX, or LTX.
6 . The composition according to claim 4 , wherein the alpha or D-gamma polyglutamated antifolate comprises pentaglutamated or hexaglutamated antifolate.
7 . The composition according to claim 5 , wherein the alpha (L-alpha or D-alpha) or D-gamma polyglutamated antifolate comprises pentaglutamated or hexaglutamated PMX, MTX, RTX, or LTX.
8 . A liposomal antifolate composition (LPA) comprising the alpha or D-gamma polyglutamated antifolate of claim 1 , wherein the liposome is optionally pegylated (PLPA).
9 . The LPA composition according to claim 8 , wherein the alpha (L-alpha or D-alpha) or D-gamma polyglutamated antifolate comprises a pentaglutamated or hexaglutamated antifolate.
10 . The LPA composition according to claim 8 , wherein the alpha (L-alpha or D-alpha) or D-gamma polyglutamated antifolate is a member selected from the group consisting of: polyglutamated methotrexate (MTX), polyglutamated pemetrexed (PMX), polyglutamated lometrexol (LTX), polyglutamated AG2034, polyglutamated raltitrexed (RTX), polyglutamated piritrexim, polyglutamated pralatrexate, polyglutamated AG2034, polyglutamated GW1843, polyglutamated aminopterin, and polyglutamated LY309887.
11 . The LPA composition according to claim 10 , wherein the alpha or D-gamma polyglutamated antifolate is polyglutamated PMX, MTX, RTX, or LTX.
12 . The LPA composition according to claim 11 , wherein the alpha or D-gamma polyglutamated antifolate comprises a pentaglutamated or hexaglutamated antifolate.
13 . The LPA composition according to claim 11 , wherein the alpha or D-gamma polyglutamated antifolate comprises pentaglutamated or hexaglutamated PMX, MTX, RTX, or LTX.
14 . The LPA according to claim 8 , wherein the liposome is anionic or neutral.
15 . The LPA composition according to claim 8 , which further comprises a targeting moiety attached to one or both of a PEG and the exterior of the liposome, and wherein the targeting moiety has a specific affinity for a surface antigen on a target cell of interest.
16 . The LPA composition according to claim 15 , wherein the targeting moiety is a polypeptide.
17 . The LPA composition according to claim 16 , wherein the targeting moiety is an antibody or a fragment of an antibody.
18 . The LPA according to claim 16 , further comprising one or more of an immunostimulatory agent, a detectable marker and a maleimide disposed on at least one of the PEG and the exterior of the liposome.
19 . The LPA composition according to claim 17 , wherein the polypeptide binds the antigen with an equilibrium dissociation constant (Kd) in a range of 0.5×10 −10 to 10×10 −6 as determined using BIACORE analysis.
20 . The LPA composition according composition according to claim 17 , wherein the polypeptide specifically binds one or more folate receptors selected from the group consisting of: folate receptor alpha (FR-α), folate receptor beta (FR-β), and folate receptor delta (FR-δ). a folate receptor.
21 . A method of killing a hyperproliferative cell that comprises contacting a hyperproliferative cell with the liposomal polyglutamated antifolate composition of claim 8 .
22 . The method of claim 21 wherein the hyperproliferative cell is a cancer cell.
23 . A method for treating cancer that comprises administering an effective amount of the liposomal polyglutamated antifolate composition of claim 8 to a subject having or at risk of having cancer.
24 . The method according to claim 23 , wherein the cancer is selected from the group consisting of: lung cancer, pancreatic, breast cancer, ovarian cancer, lung cancer, prostate cancer, head and neck cancer, gastric cancer, gastrointestinal cancer, colon cancer, esophageal cancer, cervical cancer, kidney cancer, biliary duct cancer, gallbladder cancer, and a hematologic malignancy.
25 . A method for treating cancer that comprises administering an effective amount of the PLPA composition of claim 15 to a subject having or at risk of having cancer.
26 . A method for treating cancer according to claim 25 , wherein the cancer is selected from the group consisting of: lung cancer, pancreatic, breast cancer, ovarian cancer, lung cancer, prostate cancer, head and neck cancer, gastric cancer, gastrointestinal cancer, colon cancer, esophageal cancer, cervical cancer, kidney cancer, biliary duct cancer, gallbladder cancer, and a hematologic malignancy.
27 . A method for treating cancer that comprises administering an effective amount of the PLPA composition of claim 20 to a subject having or at risk of having a cancer cell that expresses on its surface the folate receptor bound by the targeting moiety.
28 . A maintenance therapy for subjects that are undergoing or have undergone cancer therapy that comprise administering an effective amount of the liposomal polyglutamated antifolate composition of claim 8 to a subject that is undergoing or has undergone cancer therapy.
29 . A pharmaceutical composition comprising the liposomal polyglutamated antifolate composition of claim 8 .
30 . A method for treating a disorder of the immune system that comprises administering an effective amount of the liposomal polyglutamated antifolate composition of claim 8 to a subject having or at risk of having a disorder of the immune system.
31 . A method for treating an infectious that comprises administering an effective amount of the liposomal polyglutamated antifolate composition of claim 8 to a subject having or at risk of having an infectious disease.
32 . A method of delivering polyglutamated antifolate to a tumor expressing a folate receptor on its surface, the method comprising: administering the PLPA composition of claim 20 to a subject having the tumor in an amount to deliver a therapeutically effective dose of the alpha or D-gamma polyglutamated antifolate to the tumor.
33 . A method of preparing a liposomal polyglutamated antifolate composition comprising the liposomal alpha or D-gamma polyglutamated antifolate composition according to claim 8 , the method comprising: forming a mixture comprising: liposomal components and alpha or D-gamma polyglutamated antifolate in solution; homogenizing the mixture to form liposomes in the solution; and processing the mixture to form liposomes containing polyglutamated antifolate.
34 . A pharmaceutical composition comprising the liposomal polyglutamated antifolate composition of claim 8 .
35 . A targeted composition comprising the LPA composition of claim 9 .
36 . An untargeted composition comprising the LPA composition of claim 9 .