US2011111406A1PendingUtilityA1

Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly

69
Assignee: CHUGAI PHARMACEUTICAL CO LTDPriority: Apr 11, 2008Filed: Apr 10, 2009Published: May 12, 2011
Est. expiryApr 11, 2028(~1.7 yrs left)· nominal 20-yr term from priority
Inventors:Tomoyuki IgawaShinya IshiiAtsuhiko MaedaTakashi Nakai
A61P 37/00A61P 43/00C07K 16/244A61K 2039/552C12N 2760/16134C07K 2317/77A61K 39/12C07K 2317/565A61K 39/145C07K 2317/622C07K 16/248C07K 16/2866C12N 2770/20071C07K 2317/92A61K 2039/544A61K 2039/545A61K 2039/505G01N 33/6854C12N 15/1037C07K 2317/56C07K 2317/24C07K 2317/76C12N 2760/16111G01N 2500/00C07K 16/00
69
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

The present inventors discovered that antibodies having weaker antigen-binding activity at the early endosomal pH in comparison with that at the pH of plasma are capable of binding to multiple antigen molecules with a single antibody molecule, have long half-lives in plasma, and have improved durations of time in which they can bind to antigen.

Claims

exact text as granted — not AI-modified
1 . An antigen-binding molecule having a KD (pH5.8)/KD (pH7.4) value, defined as the ratio of KD for the antigen at pH 5.8 and KD for the antigen at pH 7.4, of 2 or higher. 
     
     
         2 . The antigen-binding molecule of  claim 1 , wherein the KD (pH5.8)/KD (pH7.4) value is 10 or higher. 
     
     
         3 . The antigen-binding molecule of  claim 1 , wherein the KD (pH5.8)/KD (pH7.4) value is 40 or higher. 
     
     
         4 . The antigen-binding molecule of  claim 1 , wherein at least one amino acid of the antigen-binding molecule has been substituted with histidine, or at least one histidine has been inserted into the antigen-binding molecule. 
     
     
         5 . The antigen-binding molecule of  claim 1 , wherein the antigen-binding molecule has an antagonistic activity. 
     
     
         6 . The antigen-binding molecule of  claim 1 , wherein the antigen-binding molecule binds to a membrane antigen or a soluble antigen. 
     
     
         7 . The antigen-binding molecule of  claim 1 , wherein the antigen-binding molecule is an antibody. 
     
     
         8 . A pharmaceutical composition comprising the antigen-binding molecule of  claim 1 . 
     
     
         9 . A method for improving the pharmacokinetics of an antigen-binding molecule by impairing the antigen-binding activity of the antigen-binding molecule at pH 5.8 as compared to that at pH 7.4. 
     
     
         10 . A method for increasing the number of times of antigen-binding for an antigen-binding molecule by impairing the antigen-binding activity of the antigen-binding molecule at pH 5.8 as compared to that at pH 7.4. 
     
     
         11 . A method for increasing the number of antigens that can be bound by an antigen-binding molecule by impairing the antigen-binding activity of the antigen-binding molecule at pH 5.8 as compared to that at pH 7.4. 
     
     
         12 . A method for dissociating within a cell an antigen from an extracellularly-bound antigen-binding molecule by impairing the antigen-binding activity of the antigen-binding molecule at pH 5.8 as compared to that at pH 7.4. 
     
     
         13 . A method for releasing an antigen-binding molecule, which has been bound to an antigen and internalized into a cell, in an antigen-free form to the outside of the cell by impairing the antigen-binding activity of the antigen-binding molecule at pH 5.8 as compared to that at pH 7.4. 
     
     
         14 . A method for increasing the ability of an antigen-binding molecule to eliminate an antigen in plasma by impairing the antigen-binding activity of the antigen-binding molecule at pH 5.8 as compared to that at pH 7.4. 
     
     
         15 . The method of  claim 10 , wherein the KD (pH5.8)/KD (pH7.4) value, defined as the ratio of KD for the antigen at pH 5.8 and KD for the antigen at pH 7.4, is 2 or higher. 
     
     
         16 . The method of  claim 10 , wherein the KD (pH5.8)/KD (pH7.4) value is 10 or higher. 
     
     
         17 . The method of  claim 10 , wherein the KD (pH5.8)/KD (pH7.4) value is 40 or higher. 
     
     
         18 . A method for improving the pharmacokinetics of an antigen-binding molecule by substituting at least one amino acid of the antigen-binding molecule with histidine, or inserting at least one histidine into the antigen-binding molecule. 
     
     
         19 . A method for increasing the number of times of antigen-binding for an antigen-binding molecule by substituting at least one amino acid of the antigen-binding molecule with histidine, or inserting at least one histidine into the antigen-binding molecule. 
     
     
         20 . A method for increasing the number of antigens that can be bound by an antigen-binding molecule by substituting at least one amino acid of the antigen-binding molecule with histidine, or inserting at least one histidine into the antigen-binding molecule. 
     
     
         21 . A method for dissociating within a cell an antigen from an extracellularly-bound antigen-binding molecule by substituting at least one amino acid of the antigen-binding molecule with histidine, or inserting at least one histidine into the antigen-binding molecule. 
     
     
         22 . A method for releasing an antigen-binding molecule, which has been bound to an antigen and internalized into a cell, in an antigen-free form to the outside of the cell, by substituting at least one amino acid of the antigen-binding molecule with histidine, or inserting at least one histidine into the antigen-binding molecule. 
     
     
         23 . A method for increasing the ability of an antigen-binding molecule to eliminate an antigen in plasma by substituting at least one amino acid of the antigen-binding molecule with histidine, or inserting at least one histidine into the antigen-binding molecule. 
     
     
         24 . The method of  claim 19 , wherein the histidine substitution or insertion increases the KD (pH5.8)/KD (pH7.4) value, defined as the ratio of the antigen-binding activity at pH 5.8 and the antigen-binding activity at pH 7.4, as compared to the KD (pH5.8)/KD (pH7.4) value before the histidine substitution or insertion. 
     
     
         25 . The method of  claim 10 , wherein the antigen-binding molecule has an antagonistic activity. 
     
     
         26 . The method of  claim 10 , wherein the antigen-binding molecule binds to a membrane antigen or a soluble antigen. 
     
     
         27 . The method of  claim 10 , wherein the antigen-binding molecule is an antibody. 
     
     
         28 . A method of screening for an antigen-binding molecule, which comprises the steps of:
 (a) determining the antigen-binding activity of an antigen-binding molecule at pH 6.7 to pH 10.0;   (b) determining the antigen-binding activity of the antigen-binding molecule at pH 4.0 to pH 6.5; and   (c) selecting an antigen-binding molecule whose antigen-binding activity at pH 6.7 to pH 10.0 is greater than the antigen-binding activity at pH 4.0 to pH 6.5.   
     
     
         29 . The screening method of  claim 28 , which comprises the step of selecting an antibody whose antigen-binding activity at pH 6.7 to pH 10.0 is twice or higher that of the antigen-binding activity at pH 4.0 to pH 6.5. 
     
     
         30 . A method of screening for an antigen-binding molecule, which comprises the steps of:
 (a) binding an antigen-binding molecule to an antigen under a condition of pH 6.7 to pH 10.0;   (b) placing the antigen-binding molecule that bound to the antigen of (a) under a condition of pH 4.0 to pH 6.5; and   (c) obtaining an antigen-binding molecule that dissociated under the condition of pH 4.0 to pH 6.5.   
     
     
         31 . A method of screening for an antigen-binding molecule whose binding activity at a first pH is greater than that at a second pH, which comprises the steps of:
 (a) binding an antigen-binding molecule to an antigen-immobilized column under the condition of a first pH;   (b) eluting the antigen-binding molecule that had bound to the column at the first pH from the column under the condition of a second pH; and   (c) collecting the eluted antigen-binding molecule.   
     
     
         32 . A method of screening for an antigen-binding molecule whose binding activity at a first pH is greater than that at a second pH, which comprises the steps of:
 (a) binding an antigen-binding molecule library to an antigen-immobilized column under the condition of a first pH;   (b) eluting the antigen-binding molecule from the column under the condition of a second pH;   (c) amplifying the gene encoding the eluted antigen-binding molecule; and   (d) obtaining the eluted antigen-binding molecule.   
     
     
         33 . The screening method of  claim 31 , wherein the first pH is 6.7 to 10.0 and the second pH is 4.0 to 6.5. 
     
     
         34 . The screening method of  claim 28 , wherein at least one or more amino acids of the antigen-binding molecule has been substituted with histidine, or at least one histidine has been inserted into the antigen-binding molecule. 
     
     
         35 . The screening method of  claim 28 , for obtaining an antigen-binding molecule that is superior in retention in the plasma. 
     
     
         36 . The screening method of  claim 28 , for obtaining an antigen-binding molecule that is capable of binding to an antigen two or more times. 
     
     
         37 . The screening method of  claim 28 , for obtaining an antigen-binding molecule that is capable of binding to more antigens as compared to the number of its antigen-binding sites. 
     
     
         38 . The screening method of  claim 28 , for obtaining an antigen-binding molecule that dissociates an extracellularly-bound antigen within a cell. 
     
     
         39 . The screening method of  claim 28 , for obtaining an antigen-binding molecule that is bound to an antigen and internalized into a cell, and released to the outside of the cell in an antigen-free form. 
     
     
         40 . The screening method of  claim 28 , for obtaining an antigen-binding molecule that has increased ability to eliminate an antigen in plasma. 
     
     
         41 . The screening method of  claim 28 , wherein the antigen-binding molecule is used as a pharmaceutical composition. 
     
     
         42 . The screening method of  claim 28 , wherein the antigen-binding molecule is an antibody. 
     
     
         43 . A method for producing an antigen-binding molecule, which comprises the steps of:
 (a) determining the antigen-binding activity of an antigen-binding molecule at pH 6.7 to pH 10.0;   (b) determining the antigen-binding activity of the antigen-binding molecule at pH 4.0 to pH 6.5;   (c) selecting the antigen-binding molecule whose antigen-binding activity at pH 6.7 to pH 10.0 is greater than that at pH 4.0 to pH 6.5;   (d) obtaining the gene encoding the antigen-binding molecule selected in (c); and   (e) producing the antigen-binding molecule using the gene obtained in (d).   
     
     
         44 . A method for producing an antigen-binding molecule, which comprises the steps of:
 (a) binding an antigen-binding molecule to an antigen under a condition of pH 6.7 to pH 10.0;   (b) allowing the antigen-binding molecule bound to the antigen of (a) to stand under a condition of pH 4.0 to pH 6.5;   (c) collecting the antigen-binding molecule that dissociated under the condition of pH 4.0 to pH 6.5;   (d) obtaining the gene encoding the antigen-binding molecule obtained in (c); and   (e) producing the antigen-binding molecule using the gene obtained in (d).   
     
     
         45 . A method for producing an antigen-binding molecule whose binding activity at a first pH is greater than that at a second pH, which comprises the steps of:
 (a) binding an antigen-binding molecule to an antigen-immobilized column under the first pH condition;   (b) eluting the antigen-binding molecule, which is bound to the column at the first pH, from the column under a second pH condition;   (c) collecting the eluted antigen-binding molecule;   (d) obtaining the gene encoding the antigen-binding molecule obtained in (c); and   (e) producing the antigen-binding molecule using the gene obtained in (d).   
     
     
         46 . A method for producing an antigen-binding molecule whose binding activity at a first pH is greater than that at a second pH, which comprises the steps of:
 (a) binding an antigen-binding molecule library to an antigen-immobilized column under the first pH condition;   (b) eluting the antigen-binding molecule from the column under the second pH condition;   (c) amplifying the gene encoding the eluted antigen-binding molecule;   (d) collecting the eluted antigen-binding molecule;   (e) obtaining the gene encoding the antigen-binding molecule collected in (d); and   (f) producing the antigen-binding molecule using the gene obtained in (e).   
     
     
         47 . The production method of  claim 45 , wherein the first pH is 6.7 to 10.0 and the second pH is 4.0 to 6.5. 
     
     
         48 . The production method of  claim 43 , which further comprises the step of substituting at least one amino acid of the antigen-binding molecule with histidine, or inserting at least one histidine into the antigen-binding molecule. 
     
     
         49 . The production method of  claim 43 , wherein the antigen-binding molecule is an antibody. 
     
     
         50 . A pharmaceutical composition comprising an antigen-binding molecule produced by the production method of  claim 43 . 
     
     
         51 . The method of  claim 19 , wherein the antigen-binding molecule has an antagonistic activity. 
     
     
         52 . The method of  claim 19 , wherein the antigen-binding molecule binds to a membrane antigen or a soluble antigen. 
     
     
         53 . The method of  claim 19 , wherein the antigen-binding molecule is an antibody. 
     
     
         54 . The screening method of  claim 31 , wherein at least one or more amino acids of the antigen-binding molecule has been substituted with histidine, or at least one histidine has been inserted into the antigen-binding molecule. 
     
     
         55 . The screening method of  claim 31 , for obtaining an antigen-binding molecule that is superior in retention in the plasma. 
     
     
         56 . The screening method of  claim 31 , for obtaining an antigen-binding molecule that is capable of binding to an antigen two or more times. 
     
     
         57 . The screening method of  claim 31 , for obtaining an antigen-binding molecule that is capable of binding to more antigens as compared to the number of its antigen-binding sites. 
     
     
         58 . The screening method of  claim 31 , for obtaining an antigen-binding molecule that dissociates an extracellularly-bound antigen within a cell. 
     
     
         59 . The screening method of  claim 31 , for obtaining an antigen-binding molecule that is bound to an antigen and internalized into a cell, and released to the outside of the cell in an antigen-free form. 
     
     
         60 . The screening method of  claim 31 , for obtaining an antigen-binding molecule that has increased ability to eliminate an antigen in plasma. 
     
     
         61 . The screening method of  claim 31 , wherein the antigen-binding molecule is used as a pharmaceutical composition. 
     
     
         62 . The screening method of  claim 31 , wherein the antigen-binding molecule is an antibody. 
     
     
         63 . The production method of  claim 45 , which further comprises the step of substituting at least one amino acid of the antigen-binding molecule with histidine, or inserting at least one histidine into the antigen-binding molecule. 
     
     
         64 . The production method of  claim 45 , wherein the antigen-binding molecule is an antibody. 
     
     
         65 . A pharmaceutical composition comprising an antigen-binding molecule produced by the production method of  claim 45 .

Join the waitlist — get patent alerts

Track US2011111406A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.