Antibody Buffering of a Ligand in Vivo

Abstract

Compositions and methods are provided in embodiments directed to maintaining a desired concentration range of one or more drugs in a subject, and in particular embodiments to maintaining a desired drug concentration in a body compartment in a subject, based on the surprising discovery that antibodies persist in solution in body compartments such that antibody-antigen equilibrium principles can counteract drug clearance mechanisms. One or more antibodies are selected that have a dissociation constant KD that is similar to the desired drug concentration, wherein KD is independent of the affinity of the drug for a specific drug target (receptor) in the subject.

What is claimed is: 
     
         1 . A method for maintaining a desired concentration range of one or more drugs in a subject, comprising:
 administering to the subject simultaneously or sequentially and in either order (i) at least one dose of a drug and (ii) at least one antibody, or an antigen-binding fragment thereof, that specifically binds to the drug,   wherein for said antibody an antibody dissociation constant, K D , has a value that is substantially similar to the desired concentration of the drug,   and wherein the antibody dissociation constant K D  is independent of affinity of the drug for a specific drug target in the subject.   
     
     
         2 . A method for maintaining a desired concentration range of one or more drugs in a body compartment in a subject, comprising:
 administering to the body compartment simultaneously or sequentially and in either order (i) at least one dose of a drug and (ii) at least one antibody, or an antigen-binding fragment thereof, that specifically binds to the drug,   wherein for said antibody an antibody dissociation constant, K D , has a value that is substantially similar to the desired concentration of the drug,   and wherein the antibody dissociation constant K D  is independent of affinity of the drug for a specific drug target in the subject.   
     
     
         3 . The method of  claim 2  wherein the body compartment comprises a compartment that is selected from the group consisting of a central nervous system compartment, a pericardium, a pleural space, a retro-orbital compartment, an eye compartment, a joint capsule, a lymphoid compartment, a peritoneal compartment, an intranasal compartment, a lung compartment, and a genitourinary compartment. 
     
     
         4 . The method of  claim 2  wherein the body compartment comprises a central nervous system compartment. 
     
     
         5 . The method of  claim 2  wherein the body compartment comprises a central nervous system compartment and the step of administering comprises introduction of the drug intrathecally, intraventricularly, parenchymally, subdurally, subarachnoidally or epidurally. 
     
     
         6 . The method of  claim 2  comprising administering at least two doses of the drug. 
     
     
         7 . The method of  claim 2  wherein the antibody and the drug are administered in approximately equimolar concentrations. 
     
     
         8 . The method of  claim 2  wherein the antibody and the drug are administered at an antibody-to-drug molar ratio of at least 2:1. 
     
     
         9 . The method of  claim 2  wherein the antibody is a monoclonal antibody. 
     
     
         10 . The method of  claim 2  wherein the antibody is a chimeric antibody or a humanized antibody. 
     
     
         11 . The method of  claim 2  wherein the antigen-binding fragment is selected from the group consisting of a Fab fragment, a Fab′ fragment, a (Fab′) 2  fragment, an Fd fragment, an Fv fragment, an scFv, a dAb and a diabody. 
     
     
         12 . A method according to  claim 2  wherein the step of administering comprises
 (a) administering at least one dose of a first drug and at least one first antibody, or an antigen-binding fragment thereof, that specifically binds to the first drug; and 
 (b) administering at least one dose of a second drug and at least one second antibody, or an antigen-binding fragment thereof, that specifically binds to the second drug. 
 
     
     
         13 . A method according to  claim 2  wherein the antibody, or antigen-binding fragment thereof, comprises a plurality of antibodies or antigen-binding fragments thereof, that specifically bind to the drug,
 wherein each of said antibodies has an antibody dissociation constant, K D , that has a value that is substantially similar to a desired concentration that is within the desired concentration range of the drug. 
 
     
     
         14 . A method for maintaining a desired concentration range of a drug in a central nervous system compartment in a subject, comprising:
 administering to the central nervous system compartment simultaneously or sequentially and in either order (i) at least one dose of the drug and (ii) an antibody, or an antigen-binding fragment thereof, that specifically binds to the drug,   wherein for said antibody an antibody dissociation constant, K D , has a value that is substantially similar to the desired concentration of the drug,   and wherein the antibody dissociation constant K D  is independent of affinity of the drug for a specific drug target in the subject.   
     
     
         15 . The method of  claim 14  wherein the subject has a central nervous system disease or disorder. 
     
     
         16 . The method of  claim 15  wherein the central nervous system disease or disorder is selected from the group consisting of a neoplastic condition, a neurodegenerative disease, a vascular disease and an autoimmune disease. 
     
     
         17 . The method of  claim 14  wherein the subject has a neoplastic condition of the central nervous system. 
     
     
         18 . The method of  claim 17  wherein the neoplastic condition is selected from the group consisting of glioma, astrocytoma, neurofibroma, neuroblastoma, lymphoma, a brain metastasis, and a tumor that is present in at least one of brain parenchyma, meninges, cranial nerve, pituitary gland, pineal gland, oligodendroglia, ependyma and choroid plexus. 
     
     
         19 . A method for identifying an antibody that is capable of maintaining a desired concentration range of a drug in a body compartment in a subject, comprising:
 (a) determining a desired concentration range of a drug to be maintained in a body compartment in the subject; and   (b) preparing an antibody that specifically binds to the drug and that has an antibody dissociation constant, K D , having a value that is substantially similar to the desired concentration of the drug to be maintained in the body compartment, and thereby identifying an antibody that is capable of maintaining the desired concentration range of the drug.