Reducing the risk of human anti-human antibodies through v gene manipulation

Abstract

The present embodiments relate to methods of identifying and creating human or humanized antibodies that possess a reduced risk of inducing a Human Anti-Human Antibody (HAHA) response when they are applied to a human host. Other methods are directed to predicting the likelihood of a HAHA response occurring. Methods for screening for anti-HAHA compounds are also included. Methods for determining if various conditions for administering an antibody to a subject enhance or suppress a HAHA response are also included.

1 .- 20 . (canceled) 
     
     
         21 . A method of increasing the probability that a human anti-human antibody (HAHA) response will be detected in a transgenic mouse, said method comprising:
 attaching an antigenic substance to a foreign fully human or humanized antibody; and   administering the antigenic substance that is attached to the foreign antibody to a transgenic mouse that is capable of producing at least one fully human or humanized antibody to determine if the combination induces a HAHA response.   
     
     
         22 . The method of  claim 21 , wherein the transgenic mouse comprises a collection of human immunoglobulin genes in its genome and produces the least one human or humanized antibody from said human immunoglobulin genes, wherein the collection of human immunoglobulin genes include genes that encode the fully human or humanized antibody. 
     
     
         23 . The method of  claim 21 , wherein the HAHA response comprises binding of the at least one fully human or humanized antibody to the foreign fully human or humanized antibody. 
     
     
         24 . The method of  claim 21 , wherein the foreign fully human or humanized antibody is encoded by at least one human immunoglobulin gene that is not present in the genome of the transgenic mouse. 
     
     
         25 . The method of  claim 21 , wherein the transgenic has its mouse immunoglobulin genes inactivated. 
     
     
         26 . The method of  claim 21 , wherein the transgenic mouse lacks mouse immunoglobulin V genes. 
     
     
         27 . The method of  claim 21 , wherein the transgenic mouse does not have at least one gene selected from the group consisting of: VH3-9, VH3-13, and VH3-64 genes. 
     
     
         28 . The method of  claim 21 , wherein the antigenic substance is antigenic in at least one of a mouse, a human, or a mammal. 
     
     
         29 . The method of  claim 21 , wherein the antigenic substance comprises an antigenic polypeptide. 
     
     
         30 . The method of  claim 21 , wherein the antigenic substance comprises a synthetic polypeptide having the sequence of SEQ ID NO: 9. 
     
     
         31 . The method of  claim 21 , wherein attaching the antigenic substance to the fully human or humanized antibody comprises covalently attaching the antigenic substance to the fully human or humanized antibody. 
     
     
         32 . The method of  claim 21 , wherein attaching the antigenic substance to the fully humanized antibody involves a maleimide moiety. 
     
     
         33 . The method of  claim 21 , wherein administering is performed subcutaneously, intravenously, intraperitoneally, intracranially, intradermally, intramuscularly, or orally. 
     
     
         34 . A method of increasing the probability that a human anti-human antibody (HAHA) response will be detected in a transgenic mouse, said method comprising:
 providing an antigenic substance attached to a foreign fully human or humanized antibody;   
       administering the antigenic substance attached to the foreign fully human or humanized antibody to a transgenic mouse, wherein the transgenic mouse comprises a collection of human immunoglobulin genes in its genome and produces at least one fully human or humanized antibody from said human immunoglobulin genes; and
 observing if a HAHA response is detected after an amount of time sufficient to allow for a HAHA response, wherein the HAHA response comprises binding of the at least one fully human or humanized antibody to the foreign fully human or humanized antibody. 
 
     
     
         35 . The method of  claim 34 , wherein the transgenic mouse has its mouse immunoglobulin genes inactivated. 
     
     
         36 . The method of  claim 34 , wherein the transgenic mouse lacks mouse immunoglobulin V genes. 
     
     
         37 . The method of  claim 34 , wherein the transgenic mouse does not have at least one gene selected from the group consisting of: VH3-9, VH3-13, and VH3-64 genes. 
     
     
         38 . The method of  claim 34 , wherein the antigenic substance comprises an antigenic polypeptide. 
     
     
         39 . The method of  claim 34 , wherein the antigenic substance comprises a synthetic polypeptide having the sequence of SEQ ID NO: 9. 
     
     
         40 . The method of  claim 34 , wherein the antigenic substance is covalently attached to the foreign fully human or humanized antibody.