Compositions and methods relating to universal glycoforms for enhanced antibody efficacy

Patent metadata

Field	Value
Publication number	US-10023892-B2
Application number	US-201514723297-A
Country	US
Kind code	B2
Filing date	May 27, 2015
Priority date	May 27, 2014
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

Abstract

The present disclosure relates to glycoproteins, particularly monoclonal antibodies, comprising a glycoengineered Fc region, wherein said Fc region comprises an optimized N-glycan having the structure of Sia2(α2-6)Gal2GlcNAc2Man3GlcNAc2. The glycoengineered Fc region binds FcγRIIA or FcγRIIIA with a greater affinity, relative to comparable monoclonal antibodies comprising the wild-type Fc region. The monoclonal antibodies of the invention are particularly useful in preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection where an enhanced efficacy of effector cell function (e.g., ADCC) mediated by FcγR is desired, e.g., cancer, autoimmune, infectious disease, and in enhancing the therapeutic efficacy of therapeutic antibodies the effect of which is mediated by ADCC.

First claim

What is claimed is:

1. A composition comprising an essentially homogeneous population of glycoengineered monoclonal IgG1 or IgG3 glycoantibodies or antigen binding fragments thereof, wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies or antigen binding fragments thereof have a Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 at each Asn-297 position in the Fc region, and wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies or antigen binding fragments comprising the essentially homogeneous population have less than about 2% of precursor N-glycan.

2. The composition of claim 1 , wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies or antigen binding fragments thereof exhibit an increased binding affinity for FcγRIIA or FcγRIIIA relative to a heterogeneously glycosylated population of the corresponding monoclonal IgG1 or IgG3 glycoantibodies.

3. The composition of claim 1 , wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies or antigen binding fragments thereof exhibit an increased antibody-dependent cell mediated cytotoxicity (ADCC) activity relative to a heterogeneously glycosylated population of the corresponding monoclonal IgG1 or IgG3 glycoantibodies.

4. The composition of claim 1 , wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies bind to at least an antigen associated with cancers, autoimmune or inflammatory diseases, or infectious diseases.

5. The composition of claim 1 , wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies bind to an antigen associated with cancers.

6. The composition of claim 5 , wherein the antigen is selected from the group consisting of GD2, GD3, GM2, Globo-H, SSEA-3, SSEA-4, CD16A, CD30, CD32B, CD33, CD52, EpCAM, CEA, gpA33, HER2/neu, A33, CD5, CD11c, CD19, CD20, CD22, CD23, CD27, CD40, CD45, CD79a, CD79b, CD103, CTLA4, ErbB1, ErbB3, ErbB4, VEGF receptor, TNF-α receptor, TNF-β receptor, or TNF-γ receptor, gpA33, Mucins, TAG-72, CAIX, PSMA, Folate-binding protein, VEGF, VEGFR, Integrin αVβ3, Integrin α5β1, EGFR, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP and Tenascin.

7. The composition of claim 1 , wherein the composition is produced in vitro.

8. A pharmaceutical formulation comprising a composition according to claim 1 and a pharmaceutically acceptable carrier.

9. The composition of claim 1 , wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies comprise a light chain sequence and a heavy chain sequence of Rituximab (Rituxan®).

10. The composition of claim 1 , wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies comprise a light chain sequence and a heavy chain sequence of Trastuzumab (Herceptin®).

11. A composition comprising an essentially homogeneous population of glycoengineered monoclonal IgG1 or IgG3 glycoantibodies or antigen binding fragments thereof, wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies or antigen binding fragments thereof have a Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 at each Asn-297 position in the Fc region, and wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies or antigen binding fragments comprising the essentially homogeneous population have less than about 2% of precursor N-glycan and wherein the glycoengineered monoclonal IgG1 or IgG3 glycoantibodies or antigen binding fragments thereof exhibit an increased binding affinity for FcγRIIA or FcγRIIIA or an increased antibody-dependent cell mediated cytotoxicity (ADCC) activity, or a combination thereof, relative to a heterogeneously glycosylated population of the corresponding monoclonal IgG1 or IgG3 glycoantibodies.

12. A composition comprising an essentially pure population of glycoengineered monoclonal IgG1 or IgG3 antibodies or antigen binding fragments thereof, wherein at least about 90% by weight of the glycoengineered monoclonal IgG1 or IgG3 antibodies or antigen binding fragments thereof have a Sia 2 (α2-6)Gal 2 GlcNAc 2 Man 3 GlcNAc 2 at each Asn 297 position in the Fc region.

Assignees

• Academia Sinica

Inventors

• Wong Chi-Huey
• Wu Chung-Yi
• Ma Che

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title