Compositions and methods relating to universal glycoforms for enhanced antibody efficacy

• US 10,023,892 B2
• Filed: 05/27/2015
• Issued: 07/17/2018
• Est. Priority Date: 05/27/2014
• Status: Active Grant

• Current Assignee: Academia Sinica (Government of The Republic of China)
• Original Assignee: Academia Sinica (Government of The Republic of China)
• Inventors: Wong, Chi-Huey, Wu, Chung-Yi, Ma, Che
• Primary Examiner(s): BRISTOL, LYNN ANNE
• Application Number:
  US14/723,297
• Publication Number:
  US 20150344544A1
• Time in Patent Office: 1,147 Days
• Field of Search: 4241331, 5303873, 53038815
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/42 viral
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 16/00 : Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/1018 : Orthomyxoviridae, e.g. influenza virus
• CPC Class Codes: C07K 16/18 : against material from animals or humans
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 16/32 : against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/72 : Increased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C12N 9/14 : Hydrolases (3)
• CPC Class Codes: C12N 9/24 : acting on glycosyl compounds (3.2)
• CPC Class Codes: C12P 19/14 : produced by the action of a carbohydrase (EC 3.2.x), e.g. by alpha-amylase , e.g. by cellulase, hemicellulase
• CPC Class Codes: C12Y 302/01 : Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
• CPC Class Codes: C12Y 302/01051 : Alpha-L-fucosidase (3.2.1.51)
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

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 Sia₂(α

2-6)Gal₂GlcNAc₂Man₃GlcNAc₂ 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 Fcγ

RIIA or Fcγ

RIIIA 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 α

Vβ

3, Integrin α

5β

1, 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 Sia₂(α

2-6)Gal₂GlcNAc₂Man₃GlcNAc₂ 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 Fcγ

RIIA or Fcγ

RIIIA 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 Sia₂(α

2-6)Gal₂GlcNAc₂Man₃GlcNAc₂ at each Asn 297 position in the Fc region.