US2015344585A1PendingUtilityA1

Anti-cd20 glycoantibodies and uses thereof

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Assignee: ACADEMIA SINICAPriority: May 27, 2014Filed: May 27, 2015Published: Dec 3, 2015
Est. expiryMay 27, 2034(~7.8 yrs left)· nominal 20-yr term from priority
Inventors:Chi-Huey WongChung-Yi WuMing-Hung Tsai
A61P 35/00A61P 43/00A61P 35/02A61K 2039/54C07K 2317/92C07K 2317/734A61K 2039/545C07K 16/2887C12P 21/005C07K 2317/24C12Y 302/01C07K 16/283C07K 2317/41C07K 2317/732C07K 2317/31C12Y 302/01051A61K 2039/505C12Y 302/01096
42
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Claims

Abstract

The present disclosure relates to a novel class of anti-CD20 monoclonal antibodies comprising a homogeneous population of anti-CD20 IgG molecules having the same N-glycan on each of Fc. The antibodies of the invention can be produced from anti-CD20 monoclonal antibodies by Fc glycoengineering. Importantly, the antibodies of the invention have improved therapeutic values with increased ADCC activity and increased Fc receptor binding affinity compared to the corresponding monoclonal antibodies that have not been glycoengineered.

Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A composition of anti-CD20 glycoantibodies or anti-CD20 binding fragments comprising an isolated homogeneous population of anti-CD20 IgG molecules having the same N-glycan on each of the Fc region. 
     
     
         2 . The composition of  claim 1 , wherein the anti-CD20 IgG molecule comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO: 1, and a light chain having the amino acid sequence set forth in SEQ ID NO: 2. 
     
     
         3 . The composition of  claim 1 , wherein the anti-CD20 IgG molecule comprises a light chain sequence and a heavy chain sequence of Rituximab. 
     
     
         4 . The composition of  claim 1 , wherein the anti-CD20 glycoantibodies have improved ADCC activity than Rituximab. 
     
     
         5 . The composition of  claim 4  wherein the ADCC is improved by at least about 10-fold. 
     
     
         6 . The composition of  claim 1 , wherein the anti-CD20 glycoantibodies exhibit improved binding to FcγRIIIA as compared to Rituximab. 
     
     
         7 . The composition of  claim 1 , wherein the N-glycan is attached to the Asn-297 of the Fc region. 
     
     
         8 . The composition of  claim 1 , wherein the N-glycan is free of fucose. 
     
     
         9 . The composition of  claim 1 , wherein the N-glycan comprises at least one α2-6 sialic acid. 
     
     
         10 . The composition of  claim 9 , wherein the N-glycan comprises two α2-6 sialic acids. 
     
     
         11 . The composition of  claim 1 , wherein the N-glycan is selected from the group consisting of Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-3/α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-6/α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-3/α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-6/α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-6)GalGlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-3)GalGlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-6)GalGlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-3)GalGlcNAc 3 Man 3 GlcNAc 2 , Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , GalGlcNAcMan 3 GlcNAc 2 , Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , GalGlcNAc 2 Man 3 GlcNAc 2 , GalGlcNAc 3 Man 3 GlcNAc 2 , GlcNAc 3 Man 3 GlcNAc 2 , GlcNAc 2 Man 3 GlcNAc 2 , GlcNAcMan 3 GlcNAc 2  and Man 3 GlcNAc 2 . 
     
     
         12 . The composition of  claim 11 , wherein the N-glycan is selected from the group consisting of Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-3/α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-6/α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-3/α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-6/α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-6)GalGlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-3)GalGlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-6)GalGlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-3)GalGlcNAc 3 Man 3 GlcNAc 2 , Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , GalGlcNAcMan 3 GlcNAc 2  and Gal 2 GlcNAc 3 Man 3 GlcNAc 2 . 
     
     
         13 . A pharmaceutical formulation comprising substantially pure population of anti-CD20 glycoantibodies or antigen binding fragments thereof according to  claims 1  to  12  and a pharmaceutically acceptable carrier. 
     
     
         14 . A method for the treatment of cancer in a patient wherein the method comprising administering to the patient in need thereof an effective amount of said pharmaceutical formulation according to  claim 13 . 
     
     
         15 . The method of  claim 14 , wherein the cancer is selected from the group consisting of B cell lymphomas, NHL, precursor B cell lymphoblastic leukemia/lymphoma and mature B cell neoplasms, B cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), low-grade, intermediate-grade and high-grade (FL), cutaneous follicle center lymphoma, marginal zone B cell lymphoma, MALT type marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, splenic type marginal zone B cell lymphoma, hairy cell leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, plasmacytoma, plasma cell myeloma, post-transplant lymphoproliferative disorder, Waldenstrom's macroglobulinemia, and anaplastic large-cell lymphoma (ALCL). 
     
     
         16 . The method of  claim 14 , further comprising administering to the patient a therapeutic agent. 
     
     
         17 . The method of  claim 14 , wherein the therapeutic agent comprises Rituximab. 
     
     
         18 . A method for improving disease treatment based on B-cell depletion, wherein the method comprising administering a therapeutically effective amount of said pharmaceutical composition according to  claim 13 . 
     
     
         19 . The method of  claim 18 , wherein the method comprising administering a therapeutically effective amount of said pharmaceutical composition according to  claim 13  as coadministration or coformulation. 
     
     
         20 . A method of making an anti-CD20 glycoantibody or antigen binding fragment of  claim 1 , the method comprising:
 (a) contacting an anti-CD20 monoclonal antibody with an α-fucosidase and at least one endoglycosidase, thereby yielding a defucosylated antibody having a single N-acetylglucosamine (GlcNAc), and   (b) adding a carbohydrate moiety to GlcNAc under suitable conditions.   
     
     
         21 . The method of  claim 20 , wherein the anti-CD20 monoclonal antibody is Rituximab. 
     
     
         22 . The method of  claim 20 , the anti-CD20 glycoantibodies are produced in vitro. 
     
     
         23 . The method of  claim 20 , the anti-CD20 glycoantibodies are enzymatically engineered from an antibody obtained by cell culturing. 
     
     
         24 . The method of  claim 20 , wherein the carbohydrate moiety is selected from the group consisting of Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-3/α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-6/α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-3/α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-6/α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-6)GalGlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-3)GalGlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-6)GalGlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-3)GalGlcNAc 3 Man 3 GlcNAc 2 , Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , GalGlcNAcMan 3 GlcNAc 2 , Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , GalGlcNAc 2 Man 3 GlcNAc 2 , GalGlcNAc 3 Man 3 GlcNAc 2 , GlcNAc 3 Man 3 GlcNAc 2 , GlcNAc 2 Man 3 GlcNAc 2 , GlcNAcMan 3 GlcNAc 2  and Man 3 GlcNAc 2 . 
     
     
         25 . The method of  claim 24 , wherein the carbohydrate moiety is sleeted from the group consisting of Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-3/α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-6/α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia 2 (α2-3/α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia 2 (α2-6/α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-3)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-6)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-3)Gal 2 GlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-6)GalGlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-3)GalGlcNAc 2 Man 3 GlcNAc 2 , Sia(α2-6)GalGlcNAc 3 Man 3 GlcNAc 2 , Sia(α2-3)GalGlcNAc 3 Man 3 GlcNAc 2 , Gal 2 GlcNAc 2 Man 3 GlcNAc 2 , GalGlcNAcMan 3 GlcNAc 2  and Gal 2 GlcNAc 3 Man 3 GlcNAc 2 . 
     
     
         26 . The method of  claim 20 , wherein the adding in step (b) is performed by a transglycosylase. 
     
     
         27 . The method of  claim 20 , wherein the endoglycosidase is EndoS, Endo S2, EndoH, EndoA, EndoM, EndoF, EndoF1, EndoF2 or EndoF3. 
     
     
         28 . The method of  claim 20 , wherein the α-fucosidase comprises a polypeptide having an amino acid sequence at least 90% identical to SEQ ID NO: 5. 
     
     
         29 . The method of  claim 20 , wherein the α-fucosidase is a recombinant  Bacteroides  alpha-L-fucosidase.

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