Methods and compositions for deuterated biologics

Abstract

Deuterated polymer-biomolecule conjugates and the synthesis and use of deuterated polymer-biomolecule conjugates for detecting the location of specific molecules, e.g., cell surface molecules, in a subject, and for imaging various processes within the body, for detecting the location of molecules associated with disease pathology, and for monitoring disease progression are disclosed.

What is claimed is: 
     
         1 . A conjugate comprising a deuterated polymer (D-polymer) and a biomolecule, wherein the D-polymer can be detected by MRI upon administration of the conjugate to a subject. 
     
     
         2 . The conjugate of  claim 1 , wherein the average molecular weight (Mn) of the D-polymer is between 1 kDa and 100 kDa. 
     
     
         3 . The conjugate of  claim 2 , wherein the D-polymer comprises deuterated polyethylene glycol (D-PEG). 
     
     
         4 . The conjugate of  claim 3 , wherein the D-PEG has the formula [O(CR 2 ) 2 ] n , wherein R is deuterium (D) or hydrogen (H), and n is an integer from 10 to 2500. 
     
     
         5 . The conjugate of  claim 4 , wherein the D-PEG has an OH, SH, or NH 2  group. 
     
     
         6 . The conjugate of  claim 5 , wherein the D-PEG is selected from the group consisting of: HO—(CD 2 CD 2 O) n —H (Mn 2.7); HO—(CD 2 CD 2 O) n —H (Mn 3.5); HO—(CD 2 CD 2 O) n —H (Mn 4.8); CD 3 CD 2 O—(CD 2 CD 2 O) n —H (Mn 2.7); CH 3 O—(CD 2 CD 2 O) n —H (Mn 2.2); CH 3 O—(CD 2 CD 2 O) n —H (Mn 5); CD 3 O—(CD 2 CD 2 O) n CD 2 CD 2 NH 2  (Mn 5); CH 3 O—(CD 2 CD 2 O) n CD 2 CD 2 SH (Mn 2); and CH 3 CH 2 O—(CD 2 CD 2 ) n -H. 
     
     
         7 . The conjugate of  claim 1 , wherein between about 50% and 100% of the hydrogen atoms in the D-polymer are deuterium. 
     
     
         8 . The conjugate of  claim 1 , wherein the biomolecule is or comprises a targeting moiety TM. 
     
     
         9 . The conjugate of  claim 8 , wherein the TM is a ligand, an antibody or antibody fragment, or a fibronectin based scaffold (FBS). 
     
     
         10 . The conjugate of  claim 9 , wherein TM is an antibody or antibody fragment. 
     
     
         11 . The conjugate of  claim 8 , wherein TM binds to a biological disease associated with a disease selected from the group consisting of solid cancers, hematopoietic cancers, hematological cancers, autoimmune disease, neurodegenerative disease, cardiovascular disease and pathogenic infections. 
     
     
         12 . The conjugate of  claim 11 , wherein TM binds to a tumor-associated antigen. 
     
     
         13 . The conjugate of  claim 12 , wherein the tumor associated antigen is an immune-oncology related biomarker. 
     
     
         14 . A method of obtaining an image of a D-polymer-biomolecule conjugate of according to  claim 1  in a subject, the method comprising,
 (a) administering the D-polymer-biomolecule conjugate to the subject; and 
 (b) imaging in vivo the distribution of the D-polymer-biomolecule conjugate by magnetic resonance imaging (MRI). 
 
     
     
         15 . A method of diagnosing the presence of a disease in a subject, the method comprising
 (a) administering to a subject in need thereof a D-polymer-biomolecule according to  claim 1 , which conjugate binds to a target molecule associated with the presence of the disease; and   (b) obtaining a magnetic resonance image of at least a portion of the subject to detect the presence or absence of the D-polymer-biomolecule conjugate;   
       wherein the presence and location of the D-polymer-biomolecule conjugate above background is indicative of the presence and location of the disease. 
     
     
         16 . The method of  claim 15 , wherein the disease is selected from the group consisting of solid cancers, hematopoietic cancers, hematological cancers, autoimmune disease, neurodegenerative disease cardiovascular disease, and pathogenic infection. 
     
     
         17 . A method of monitoring the progress of a disease in a subject, the method comprising
 (a) administering to the subject a D-polymer-biomolecule conjugate according to  claim 1 , which conjugate binds to a target molecule associated with the presence of the disease at a first time point and obtaining an image of at least a portion of the subject to determine the amount of the diseased cells or tissue; and   (b) administering to the subject the D-polymer-biomolecule conjugate at one or more subsequent time points and obtaining an image of at least a portion of the subject at each time point,   
       wherein the dimension and location of the diseased cells or tissue at each time point is indicative of the progress of the disease. 
     
     
         18 . The method of  claim 17 , wherein the disease is selected from the group consisting of solid cancers, hematopoietic cancers, hematological cancers, autoimmune disease, neurodegenerative disease cardiovascular disease, and pathogenic infection. 
     
     
         19 . A method of determining the distribution of a deuterated molecule in a subject, the method comprising
 (a) orally administering the deuterated molecule to the subject and   (b) imaging in vivo the distribution of the deuterated molecule by magnetic resonance imaging (MRI).   
     
     
         20 . A method according to  claim 19 , wherein the deuterated molecule is D-PEG.