Dual receptor antagonistic antigen-binding proteins and uses thereof

Abstract

This disclosure related to antagonistic dual receptor antigen-binding proteins, e.g. antibodies and methods of using the dual receptor antibodies for treatment of pathological diseases. The dual receptor antibodies may comprise an antibody to ActRII receptors and may be used to treat pathological condition. The pathological conditions can comprise muscle wasting diseases or any disease that requires stimulation of muscle growth.

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         36 . A method of reducing or blocking myostatin, activin A or GDF-11 activity comprising administering a therapeutically effective amount of the antigen-binding protein or a pharmaceutical composition containing the antigen binding protein comprising an isolated antigen-binding protein comprising a first polypeptide having at least 97% identity to SEQ ID NO: 15 and a second polypeptide having at least 97% sequence identity to SEQ ID NO: 16, to a subject in need of such treatment. 
     
     
         37 . A method of increasing lean muscle mass or increasing the ratio of lean muscle mass to fat mass in a subject in need of such treatment comprising administering an effective amount the antigen-binding protein or a pharmaceutical composition containing the antigen binding protein comprising an isolated antigen-binding protein comprising a first polypeptide having at least 97% identity to SEQ ID NO: 15 and a second polypeptide having at least 97% sequence identity to SEQ ID NO: 16,
 to a subject in need of such treatment.   
     
     
         38 . A method of treating or preventing a muscle wasting disease in a subject suffering from such a disorder comprising administering an effective amount of a therapeutic composition containing the antigen-binding polypeptide comprising an isolated antigen-binding protein comprising a first polypeptide having at least 97% identity to SEQ ID NO: 15 and a second polypeptide having at least 97% sequence identity to SEQ ID NO: 16,
 to the subject. 
 
     
     
         39 . The method of  claim 38  wherein the muscle wasting disease comprises cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis, congestive obstructive pulmonary disease, chronic hearing failure, chemical cachexia, cachexia from HIV/AIDS, renal failure, uremia, rheumatoid arthritis, age-related sacopenia, age-related failty, organ atrophy, carpal tunnel syndrome, androgen deprivation, or muscle-wasting due to inactivity from prolonged bed rest, spinal cord injury, stroke, bone fracture, burns, aging or insulin resistance. 
     
     
         40 . An isolated antigen-binding protein comprising an isolated antigen-binding protein comprising a first polypeptide having at least 97% identity to SEQ ID NO: 15 and a second polypeptide having at least 97% sequence identity to SEQ ID NO: 16,
 wherein said antigen-binding protein has a K D  for ActRIIB of 10 pM or less in BIAcore assay.   
     
     
         41 . The antigen-binding protein of  claim 40  wherein said antigen-binding protein has a K D  for ActRIIB of 1 pM or less. 
     
     
         42 . An isolated antigen-binding protein comprising an isolated antigen-binding protein comprising a first polypeptide having at least 97% identity to SEQ ID NO: 15 and a second polypeptide having at least 97% sequence identity to SEQ ID NO: 16,
 wherein said antigen-binding protein has a K D  for ActRIIA of 4 nM or less in BIAcore assay.   
     
     
         43 . The antigen-binding protein of  claim 42  wherein said antigen-binding protein also has a K D  for ActRIIA of 1 pM or less. 
     
     
         44 . The antigen-binding protein of  claim 42 , wherein said antigen-binding protein has a K D  for ActRIIB and ActRIIA of 1 pM or less in a BIAcore assay. 
     
     
         45 . An isolated antigen-binding protein comprising an isolated antigen-binding protein comprising a first polypeptide having at least 97% identity to SEQ ID NO: 15 and a second polypeptide having at least 97% sequence identity to SEQ ID NO: 16,
 wherein said antigen-binding protein has an IC 50  for ActRIIB of 8 nm or less in a cell-based assay.   
     
     
         46 . The antigen-binding protein of  claim 40  wherein said antigen-binding protein has an IC 50  for ActRIIB of 2 nM or less. 
     
     
         47 . An isolated antigen-binding protein comprising an isolated antigen-binding protein comprising a first polypeptide having at least 97% identity to SEQ ID NO: 15 and a second polypeptide having at least 97% sequence identity to SEQ ID NO: 16,
 wherein said antigen-binding protein has an IC 50  for ActRIIA of 2 nM or less in a cell-based assay.   
     
     
         48 . The antigen-binding protein of  claim 42  wherein said antigen-binding protein also has an IC 50  for ActRIIA of 1 nM or less. 
     
     
         49 . An antigen-binding protein of  claim 42 , wherein said antigen-binding protein has a IC 50  for ActRIIB of 2 nM or less and a IC 50 ActRIIA of 1 nM or less in a cell-based assay. 
     
     
         50 . The antigen-binding protein comprising an isolated antigen-binding protein comprising a first polypeptide having at least 97% identity to SEQ ID NO: 15 and a second polypeptide having at least 97% sequence identity to SEQ ID NO: 16,
 wherein the antigen-binding protein is an antagonistic dual-receptor antibody.   
     
     
         51 . The antagonistic dual-receptor antibody of  claim 50  wherein the dual-receptor antibody is a human antibody. 
     
     
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