Compositions and methods relating to glucagon receptor antibodies
First Claim
Patent Images
1. An isolated antigen binding protein comprising an amino acid sequence selected from the group consisting of:
- a. a light chain CDR3 comprising a sequence selected from the group consisting of;
i. a light chain CDR3 sequence that differs by no more than a total of three amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the light chain CDR3 sequences of L1-L23, SEQ ID NOs;
72;
74, 76, 78, 80, 83, 85, 87, 89, 91, 93, 95, 97, 100;
ii. L Q X21 N S X22 P L T (SEQ ID NO;
208); and
iii. Q A W D S X23 T V X24 (SEQ ID NO;
209);
b. a heavy chain CDR3 sequence comprising a sequence selected from the group consisting of;
i. a heavy chain CDR3 sequence that differs by no more than a total of four amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the heavy chain CDR3 sequences of H1-H23, SEQ ID NOs;
165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199;
ii. E X25 X26 X27 Y D I L T G Y X28 X29 Y Y G X30 D V (SEQ ID NO;
210); and
iii. X31 G G G F D Y (SEQ ID NO;
211);
orc. the light chain CDR3 sequence of (a) and the heavy chain CDR3 sequence of (b);
wherein,X21 is a histidine residue, or a glutamine residue,X22 is an asparagine residue, an aspartate residue, or a tyrosine residue,X23 is an asparagine residue or a serine residue,X24 is an isoleucine residue or a valine residue,X25 is a lysine residue, a glutamate residue, or a proline residue,X26 is an aspartate residue, a threonine residue, a glutamine residue, or a proline residue,X27 is a histidine residue or a tyrosine residue,X28 is an asparagine residue, a histidine residue, an aspartate residue, or a phenylalanine residue,X29 is a tyrosine residue, a histidine residue, or an asparagine residue,X30 is a leucine residue or a methionine residue,X31 is a leucine residue or a methionine residue,and wherein said antigen binding protein specifically binds to the human glucagon receptor.
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Abstract
The present disclosure provides compositions and methods relating to antigen binding proteins, in particular, antibodies which specifically bind to the human glucagon receptor. The disclosure provides nucleic acids encoding such antigen binding proteins and antibodies and methods of making and using such antibodies including methods of treating and preventing type 2 diabetes and related disorders by administering such antibodies to a subject in need of such treatment.
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Citations
25 Claims
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1. An isolated antigen binding protein comprising an amino acid sequence selected from the group consisting of:
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a. a light chain CDR3 comprising a sequence selected from the group consisting of; i. a light chain CDR3 sequence that differs by no more than a total of three amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the light chain CDR3 sequences of L1-L23, SEQ ID NOs;
72;
74, 76, 78, 80, 83, 85, 87, 89, 91, 93, 95, 97, 100;ii. L Q X21 N S X22 P L T (SEQ ID NO;
208); andiii. Q A W D S X23 T V X24 (SEQ ID NO;
209);b. a heavy chain CDR3 sequence comprising a sequence selected from the group consisting of; i. a heavy chain CDR3 sequence that differs by no more than a total of four amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the heavy chain CDR3 sequences of H1-H23, SEQ ID NOs;
165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199;ii. E X25 X26 X27 Y D I L T G Y X28 X29 Y Y G X30 D V (SEQ ID NO;
210); andiii. X31 G G G F D Y (SEQ ID NO;
211);
orc. the light chain CDR3 sequence of (a) and the heavy chain CDR3 sequence of (b);
wherein,X21 is a histidine residue, or a glutamine residue, X22 is an asparagine residue, an aspartate residue, or a tyrosine residue, X23 is an asparagine residue or a serine residue, X24 is an isoleucine residue or a valine residue, X25 is a lysine residue, a glutamate residue, or a proline residue, X26 is an aspartate residue, a threonine residue, a glutamine residue, or a proline residue, X27 is a histidine residue or a tyrosine residue, X28 is an asparagine residue, a histidine residue, an aspartate residue, or a phenylalanine residue, X29 is a tyrosine residue, a histidine residue, or an asparagine residue, X30 is a leucine residue or a methionine residue, X31 is a leucine residue or a methionine residue, and wherein said antigen binding protein specifically binds to the human glucagon receptor. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)
X1 is a serine residue or a threonine residue, X2 is an arginine residue or a serine residue, X3 is an aspartate residue or an alanine residue, X4 is a glycine residue or an aspartate residue, X5 is a leucine residue or a phenylalanine residue, X6 is a valine residue or an alanine residue, b. a light chain CDR2 sequence selected from the group consisting of; i. a light chain CDR2 that differs by no more than two amino acid additions, substitutions, and/or deletions from a CDR2 sequence of L1-L23, SEQ ID NOs;
43, 45, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, and 70;ii. A A S S L X9 S (SEQ ID NO;
204); andiii. Q X10 X11 K R P S (SEQ ID NO;
205);
whereinX9 is a glutamine residue or a glutamate residue, X10 is a serine residue or a threonine residue, X11 is a threonine residue, or a serine residue, c. a heavy chain CDR1 sequence selected from the group consisting of; i. a heavy chain CDR1 that differs by no more than two amino acid additions, substitutions, and/or deletions from a CDR1 sequence of H1-H23, SEQ ID NOs;
102, 104, 106, 108, 111, 113, 115, 117, 118, 120 and 122; andii. X7 Y X8 M H (SEQ ID NO;
203);
whereinX7 is a serine residue or a threonine residue, X8 is a glycine residue or an aspartate residue; and d. a heavy chain CDR2 selected from the group consisting of; i. a heavy sequence that differs by no more than three amino acid additions, substitutions, and/or deletions from a CDR2 sequence of H1-H23, SEQ ID NOs;
124, 126, 128, 130, 132, 134, 136, 138, 140, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, and 163;ii. X12 I W X13 D G S X14 K Y Y X15 D S V K G (SEQ ID NO;
206);iii. X16 I S X17 D G S X18 K Y X19 X20 D S V K G (SEQ ID NO;
207);wherein X12 is a serine residue, a phenylalanine residue, a valine residue, or a glutamate residue, X13 is a tyrosine residue or an asparagine residue, X14 is an asparagine residue or a glutamate residue, X15 is a valine residue or an alanine residue, X16 is a valine residue or a phenylalanine residue, X17 is a histidine residue, an aspartate residue, or a tyrosine residue X18 is an aspartate residue, an asparagine residue, or a histidine residue, X19 is a tyrosine residue, or a serine residue, X20 is an alanine residue or a glycine residue, e. the light chain CDR1 of (a) and the light chain CDR2 of (b); f. the light chain CDR1 of (a) and the heavy chain CDR1 of (c); g. the light chain CDR1 of (a) and the heavy chain CDR2 of (d); h. the light chain CDR1 (b) and the heavy chain CDR1 of (c); i. the heavy chain CDR1 of (c) and the heavy chain CDR2 of (d); j. the light chain CDR2 of (b) and the heavy chain CDR2 of (d); k. the light chain CDR1 of (a), the light chain CDR2 of (b), and the heavy chain CDR1 of (c); l. the light chain CDR2 of (b), the heavy CDR1 of (c), and the heavy chain CDR2 of (d); m. the light chain CDR1 of (a), the heavy chain CDR1 of (c), and the heavy chain CDR2 of (d);
orn. the light chain CDR1 of (a), the light chain CDR2 of (b), the heavy chain CDR2 of (c), and the heavy chain CDR2 of (d), wherein said antigen binding protein specifically binds to the human glucagon receptor.
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3. The isolated antigen binding protein of claim 1, comprising either:
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a. a light chain variable domain comprising; i. a light chain CDR1 sequence selected from SEQ ID NOs;
10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 41;ii. a light chain CDR2 sequence selected from SEQ ID NOs;
43, 45, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, and 70;iii. a light chain CDR3 sequence selected from SEQ ID NOs;
72, 74, 76, 78, 80, 83, 85, 87, 89, 91, 93, 95, 97, and 100; andb. a heavy chain variable domain comprising; i. a heavy chain CDR1 sequence selected from SEQ ID NOs;
102, 104, 106, 108, 111, 113, 115, 117, 118, 120, and 122;ii. a heavy chain CDR2 sequence selected from SEQ ID NOs;
124, 126, 128, 130, 132, 134, 136, 138, 140, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, and 163; andiii. a heavy chain CDR3 sequence selected from SEQ ID NOs;
165, 167, 169, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, and 199;
orc. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antigen binding protein specifically binds to human glucagon receptor.
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4. The isolated antigen binding protein of claim 1 comprising either:
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a. a light chain variable domain sequence selected from the group consisting of; i. amino acids having a sequence at least 80% identical to a light chain variable domain sequence selected from L1-L23, SEQ ID NOs;
213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, and 257;ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding the light chain variable domain sequence of L1-L23, SEQ ID NOs;
212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, and 256;iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a light chain variable domain sequence of L1-L23 of SEQ ID NOs;
212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, and 256;b. a heavy chain variable domain sequence selected from the group consisting of; i. a sequence of amino acids that is at least 80% identical to a heavy chain variable domain sequence of H1-H23 of SEQ ID NOs;
259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, and 303;ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding the heavy chain variable domain sequence of H1-H23, SEQ ID NOs;
258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 292, 294, 296, 298, 300, and 302;iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a heavy chain variable domain sequence of H1-H23, SEQ ID NOs;
258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 292, 294, 296, 298, 300, and 302;
orc. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antigen binding protein binds to the human glucagon receptor.
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5. The isolated antigen binding protein of claim 4, comprising either:
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a. a light chain variable domain sequence selected from the group consisting of;
L1-L23 of SEQ ID NOs;
213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241. 243, 245, 247, 249, 251, 253, 255, and 257;b. a heavy chain variable domain sequence selected from the group consisting of;
H1-H23 of SEQ ID NOs;
259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, and 303;
orc. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antigen binding protein specifically binds to the human glucagon receptor.
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6. The antigen binding protein of claim 5, wherein the light chain variable domain and a heavy chain variable domain are selected from the group of combinations consisting of:
- L1H1, L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, and L23H23,
wherein the antigen binding protein specifically binds to the human glucagon receptor.
- L1H1, L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, and L23H23,
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7. The antigen binding protein of claim 6, further comprising:
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a. the light chain constant sequence of SEQ ID NO;
305;b. the light chain constant sequence of SEQ ID NO;
307;c. the heavy chain constant sequence of SEQ ID NO;
309;d. the light chain constant sequence of SEQ ID NO;
305 and the heavy chain constant sequence of SEQ ID NO;
309, ore. the light chain constant sequence of SEQ ID NO;
307 and the heavy chain constant sequence of SEQ ID NO;
309.
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8. The isolated binding protein of claim 1, wherein the antigen binding protein is selected from the group consisting of a human antibody, a humanized antibody, chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an F(fa′
- )x fragment, a domain antibody, an IgD antibody, an IgE antibody, and IgM antibody, and IgG1 antibody, and IgG2 antibody, and IgG3 antibody, and IgG4 antibody, and IgG4 antibody having at least one mutation in the hinge region.
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9. The antigen binding protein of claim 1, that, when bound to the human glucagon receptor:
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a. binds to the human glucagon receptor with substantially the same Kd as a reference antibody; b. inhibits glucagon stimulation of the human glucagon receptor with substantially the same IC50 as said reference antibody;
orc. cross-competes for binding with said reference antibody on the human glucagon receptor, wherein said reference antibody comprises a combination of light chain and heavy chain variable domain sequences selected from the group consisting of L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L11H11, L12H12, L13H13, L15H15, L21H21, and L22H22.
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12. A pharmaceutical composition comprising the antigen binding protein of claim 1 in admixture with a pharmaceutically acceptable carrier thereof.
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14. An isolated nucleic acid comprising a polynucleotide sequence encoding the light chain variable domain, the heavy chain variable domain, or both, of the antigen binding protein of claim 4.
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15. The isolated nucleic acid of claim 14, wherein the sequence is selected from L1-L23, SEQ ID NOs:
- 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, and 256;
H1-H23, SEQ ID NOs;
258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, and 302, or both.
- 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, and 256;
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16. An expression vector comprising the nucleic acid of claim 14.
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17. An isolated cell comprising the nucleic acid of claim 14.
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18. The isolated cell of claim 17, wherein the chromosome of the cell comprises the nucleic acid.
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19. The isolated cell of claim 18, wherein the cell is a hybridoma.
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20. The isolated cell of claim 17, wherein an expression vector comprises said nucleic acid.
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21. A method of producing an antigen binding protein that specifically binds to the human glucagon receptor comprising incubating the host cell of claim 17 under conditions that allow it to express the antigen binding protein.
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22. A method of preventing or treating a condition in a subject in need of such treatment comprising administering a therapeutically effective amount of the composition of claim 12 to the subject, wherein the condition is treatable by lowering blood glucose.
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23. The method of claim 22, wherein the condition is selected from hyperglycemia, hyperinsulinemia, impaired fasting glucose, impaired glucose tolerance, dyslipodemia, and type 2 diabetes.
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10. An isolated human antibody that, when bound to the human glucagon receptor:
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a. binds to the human glucagon receptor with substantially the same Kd as a reference antibody; b. inhibits glucagon stimulation of the human glucagon receptor with substantially the same IC50 as said reference antibody;
orc. cross-competes for binding with said reference antibody on human glucagon receptor, wherein said reference antibody is selected from the group consisting of A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-11, A-12, A-13, A-15, A-21, and A-22. - View Dependent Claims (11, 13, 24, 25)
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Specification