HIGHLY GALACTOSYLATED ANTI-TNF-ALPHA ANTIBODIES AND USES THEREOF

• US 20190309058A1
• Filed: 11/15/2018
• Published: 10/10/2019
• Est. Priority Date: 02/13/2013
• Status: Abandoned Application

• Current Assignee: Laboratoire francais du Fractionnement et des Biotechnologies
• Original Assignee: Laboratoire francais du Fractionnement et des Biotechnologies
• Inventors: Meade, Harry M., Chen, Li-How
• Application Number:
  US16/192,273
• Publication Number:
  US 20190309058A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 39/39508 from milk, i.e. lactoglobulins
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07K 16/04 from milk
• CPC Class Codes: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 2317/12 isolated from milk
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• 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 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

In one aspect, the disclosure relates to highly galactosylated anti-TNF-alpha antibodies and compositions thereof. In one aspect, the disclosure relates to populations of anti-TNF-alpha antibodies with a high level of galactosylation, and compositions thereof. In one aspect, the disclosure relates to methods of production and use of highly galactosylated anti-TNF-alpha antibodies and populations of anti-TNF-alpha antibodies with a high level of galactosylation. In some embodiments, the anti-TNF-alpha antibody is adalimumab.

Claims

1-77. -77. (canceled)

78. A composition, comprising a population of antibodies,

wherein the antibodies in the population of antibodies are anti-TNF-alpha antibodies produced in mammary gland epithelial cells of a transgenic non-human mammal;

wherein the level of galactosylation of the antibodies in the population of antibodies comprises at least 5% mono-galactosylated N-glycans or at least 10% bigalactosylated N-glycans;

wherein the level of fucosylation of the antibodies in the population of antibodies is at least 30%; and

wherein the antibodies in the population of antibodies comprise a heavy chain (HC), which comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) 100% identical to HC CDR1, HC CDR2 and HC CDR3 of SEQ ID NO;

1 and a light chain (LC), which comprises a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3) 100% identical to LC CDR1, LC CDR2 and LC CDR3 of SEQ ID NO;

2.

79. The composition of claim 78, wherein at least 25% of the antibodies in the population comprise mono-galactosylated N-glycans and at least 35% of the antibodies in the population comprise bi-galactosylated N-glycans.

80. The composition of claim 78, wherein the level of fucosylation of the antibodies in the population is at least 40%.

81. The composition of claim 78, wherein the level of fucosylation of the antibodies in the population is 30.4%-78.2%.

82. The composition of claim 78, wherein the level of fucosylation of the antibodies in the population is at least 50%.

83. The composition of claim 78, wherein the level of fucosylation of the antibodies in the population is at least 60%.

84. The composition of claim 78, wherein the level of fucosylation of the antibodies in the population is at least 70%.

85. The composition of claim 78, wherein the level of fucosylation of the antibodies in the population is at least 80%.

86. The composition of claim 78, wherein the level of fucosylation of the antibodies in the population is at least 90%.

87. The composition of claim 78, wherein the ratio of the level of galactosylation of the antibodies in the population to the level of fucosylation of the antibodies in the population is between 1.0 and 1.4.

88. The composition of claim 78, wherein the population of antibodies has an increased level of complement dependent cytotoxicity (CDC) activity when compared to a population of antibodies not produced in mammary gland epithelial cells.

89. The composition of claim 78, wherein the population of antibodies has an increased level of antibody-dependent cellular cytotoxicity (ADCC) activity when compared to a population of antibodies not produced in mammary gland epithelial cells.

90. The composition of claim 78, wherein the transgenic non-human mammal is a goat, sheep, camel, cow, pig, rabbit, rat, mouse or llama.

91. The composition of claim 90, wherein the transgenic non-human mammal is a goat.

92. A composition, comprising:

a population of antibodies,

wherein the antibodies in the population of antibodies are anti-TNF-alpha antibodies produced in mammary gland epithelial cells of a transgenic non-human mammal;

wherein at least 30% of the antibodies in the population of antibodies contain at least one oligomannose;

wherein the level of fucosylation of the antibodies in the population of antibodies is at least 30%; and

wherein the antibodies in the population of antibodies comprise a heavy chain (HC), which comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) 100% identical to HC CDR1, HC CDR2 and HC CDR3 of SEQ ID NO;

1 and a light chain (LC), which comprises a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3) 100% identical to LC CDR1, LC CDR2 and LC CDR3 of SEQ ID NO;

2.

93. The composition of claim 92, wherein the antibodies in the population of antibodies exhibit a high mannose glycosylation pattern.

94. The composition of claim 93, wherein at least one chain of the antibodies in the population of antibodies contains an oligomannose and is non-fucosylated.

95. The composition of claim 92, wherein the major carbohydrate of the antibodies in the population of antibodies is non-fucosylated.

96. The composition of claim 92, wherein the transgenic non-human mammal is a goat, sheep, camel, cow, pig, rabbit, rat, mouse or llama.

97. The composition of claim 96, wherein the transgenic non-human mammal is a goat.