Anti-Marinobufagenin Antibodies and Uses Thereof

Abstract

The present disclosure provides chimeric, humanized and human monoclonal antibodies (mAbs) and fragments thereof that specifically bind to marinobufagenin (MBG) with high affinity. The anti-MBG mAbs and fragments thereof can be used to treat MBG-associated disorders, including hypertensive disorders and fibrotic disorders, optionally in combination with an additional therapeutic agent. Furthermore, the anti-MBG mAbs and fragments thereof can be used for diagnostic purposes, including to detect MBG in biological samples and to diagnose MBG-associated disorders.

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         22 . A method for treating a subject, comprising the steps of: providing a subject wherein the subject has an MBG-associated disorder that has an elevated level of marinobufagenin, administering to the subject an anti-marinobufagenin antibody, wherein the anti-marinobufagenin antibody binds a marinobufagenin in the subject, whereby the MBG-associated disorder is treated. 
     
     
         23 . The method of  claim 22 , wherein the anti-marinobufagenin antibody is a human antibody. 
     
     
         24 . The method of  claim 23 , wherein the human antibody is selected from the group consisting of a 201/202, a 203/204, a 205/207, 206/208, a 236/237, a 238/239, a 240/241, a R4CE-1E, a R4CE-7G, a R4CE-10H, a 1B-6C, a 1B-6E, a 2A-5A, and a 2A-F8. 
     
     
         25 . The method of  claim 22 , wherein the anti-marinobufagenin antibody is selected from the group consisting of a H1L1, a H2L1, a H3L1, a H1L2, a H2L2, a H3 L1, and a H3L2. 
     
     
         26 . The method of  claim 25 , wherein the anti-marinobufagenin antibody is a H3L2. 
     
     
         27 . The method of  claim 22 , wherein the MBG-associated disorder is a pre-eclampsia, wherein the subject has a hypertension. 
     
     
         28 . The method of  claim 27 , wherein the antibody is selected from the group consisting of a 201/202, a 203/204, a 205/207, 206/208, a 236/237, a 238/239, a 240/241, a R4CE-1E, a R4CE-7G, a R4CE-10H, a 1B-6C, a 1B-6E, a 2A-5A, a 2A-F8, a H1L1, a H2L1, a H3L1, a H1L2, a H2L2, a H3 L1, and a H3L2. 
     
     
         29 . The method of  claim 28 , wherein the anti-marinobufagenin antibody is a H3L2. 
     
     
         30 . The method of  claim 27 , further comprising the step of lowering a blood pressure of the subject whereby the hypertension of the subject is treated. 
     
     
         31 . The method  claim 27 , wherein the preeclampsia is associated with a vascular fibrosis, and further comprising the step of reducing the vascular fibrosis. 
     
     
         32 . The method of  claim 22 , wherein the MBG-associated disorder is a diabetic nephropathy associated with an insulin resistance, and a glucose intolerance. 
     
     
         33 . The method of  claim 32 , wherein the human antibody is selected from the group consisting of a 201/202, a 203/204, a 205/207, 206/208, a 236/237, a 238/239, a 240/241, a R4CE-1E, a R4CE-7G, a R4CE-10H, a 1B-6C, a 1B-6E, a 2A-5A, a 2A-F8, a H1L1, a H2L1, a H3L1, a H1L2, a H2L2, a H3 L1, and a H3L2. 
     
     
         34 . The method of  claim 33 , wherein the anti-marinobufagenin antibody is a H3L2. 
     
     
         35 . The method of  claim 32 , wherein the binding of the marinobufagenin by the anti-marinobufagenin antibody reduces the insulin resistance of the subject. 
     
     
         36 . The method of  claim 32 , wherein the binding of the marinobufagenin by the anti-marinobufagenin antibody reduces the glucose intolerance of the subject. 
     
     
         37 . The method of  claim 22 , wherein the MBG-associated disorder is a fibrosis. 
     
     
         38 . The method of  claim 37 , wherein the human antibody is selected from the group consisting of a 201/202, a 203/204, a 205/207, 206/208, a 236/237, a 238/239, a 240/241, a R4CE-1E, a R4CE-7G, a R4CE-10H, a 1B-6C, a 1B-6E, a 2A-5A, a 2A-F8, a H1L1, a H2L1, a H3L1, a H1L2, a H2L2, a H3 L1, and a H3L2. 
     
     
         39 . The method of  claim 38 , wherein the anti-marinobufagenin antibody is a H3L2. 
     
     
         40 . The method of  claim 37 , wherein the fibrosis is associated with an increased collagen production in the subject at a site of fibrosis, and wherein the binding of the marinobufagenin by the anti-marinobufagenin antibody reduces the collagen production in the subject at the site of fibrosis. 
     
     
         41 . The method of  claim 37 , wherein the fibrosis associated with a tubulointerstitial fibrosis in a kidney, and wherein the binding of the marinobufagenin by the anti-marinobufagenin antibody reduces the tubulointerstitial fibrosis in the kidney.