US2017002075A1PendingUtilityA1
Antibodies to receptor of advanced glycation end products (rage) and uses thereof
Est. expiryMay 9, 2028(~1.8 yrs left)· nominal 20-yr term from priority
Inventors:Jijie GuChung-Ming HsiehZhen WuEnrico L. DigiammarinoFeng LuoGerard B. FoxJohn E. HarlanMartin SchmidtRalf LoebbertReinhold MuellerUlrich EbertVolker Nimmrich
A61P 37/00A61P 25/16A61P 25/00A61P 25/14A61P 25/18A61P 27/06A61P 25/24A61P 25/28A61P 29/00C07K 16/464C07K 2317/565A61P 21/04C07K 2317/92C07K 2317/24C12P 21/005C07K 16/2803C07K 16/00C07K 2317/76C07K 2317/14A61K 2039/505C07K 2317/34C07K 2317/56C07K 16/28C07K 2317/567A61P 21/02A61P 19/02A61P 13/12A61K 39/395Y02A50/30
48
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Claims
Abstract
The present application relates to isolated proteins, particularly monoclonal antibodies, in particular CDR-grafted, humanized antibodies which bind to RAGE protein. Specifically, these antibodies have the ability to inhibit the binding of RAGE to its various ligands. The antibodies or portions thereof of described in the present application are useful for treating a disease or disorder characterized by or induced by pathophysiological ligands of RAGE, for example missfolded proteins like amyloid β and advanced glycation-end-products.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . An isolated monoclonal antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a human RAGE molecule, said antigen binding domain comprising at least one CDR comprising an amino acid sequence selected from:
a) the CDR-H3 group of amino acid sequences consisting of SEQ ID NO.: 4, 12 and 20; modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences; and/or b) the CDR-L3 group of amino acid sequences consisting of SEQ ID NO.: 8, 16 and 24; and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.
2 . The antibody according to claim 1 , further comprising at least one CDR comprising an amino acid sequence selected from the CDR-H1 group consisting of SEQ ID NO: 2, 10, 18; or selected from the CDR-H2 group consisting of SEQ ID NO: 3, 11, 19; or selected from the CDR-L1 group consisting of SEQ ID NO: 6, 14, 22; or selected from the CDR-L2 group consisting of SEQ ID NO: 7, 15, 23;
and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.
3 . The antibody according to claim 2 , comprising at least 3 CDRs which are selected from a variable domain CDR set consisting of:
VH 7F9 set
VH 7F9 CDR-H1
Residues 31-35 of SEQ ID NO.: 1
SEQ ID
NO: 2
VH 7F9 CDR-H2
Residues 50-68 of SEQ ID NO.: 1
SEQ ID
NO: 3
VH 7F9 CDR-H3
Residues 101-108 of SEQ ID NO.: 1
SEQ ID
NO: 4
VL 7F9 set
VL 7F9 CDR-L1
Residues 24-34 of SEQ ID NO.: 5
SEQ ID
NO: 6
VL 7F9 CDR-L2
Residues 50-56 of SEQ ID NO.: 5
SEQ ID
NO: 7
VL 7F9 CDR-L3
Residues 89-97 of SEQ ID NO.: 5
SEQ ID
NO: 8
VH 11E6 set
VH 11E6 CDR-H1
Residues 31-35 of SEQ ID NO.: 9
SEQ ID
NO: 10
VH 11E6 CDR-H2
Residues 50-66 of SEQ ID NO.: 9
SEQ ID
NO: 11
VH 11E6 CDR-H3
Residues 99-109 of SEQ ID NO.: 9
SEQ ID
NO: 12
VL 11E6 set
VL 11E6 CDR-L1
Residues 24-34 of SEQ ID NO.: 13
SEQ ID
NO: 14
VL 11E6 CDR-L2
Residues 50-56 of SEQ ID NO.: 13
SEQ ID
NO: 15
VL 11E6 CDR-L3
Residues 89-97 of SEQ ID NO.: 13
SEQ ID
NO: 16
VH 4E5 set
VH 4E5 CDR-H1
Residues 31-35 of SEQ ID NO.: 17
SEQ ID
NO: 18
VH 4E5 CDR-H2
Residues 50-66 of SEQ ID NO.: 17
SEQ ID
NO: 19
VH 4E5 CDR-H3
Residues 99-109 of SEQ ID NO.: 17
SEQ ID
NO: 20
VL 4E5 set
VL 4E5 CDR-L1
Residues 24-34 of SEQ ID NO.: 21
SEQ ID
NO: 22
VL 4E5 CDR-L2
Residues 50-56 of SEQ ID NO.: 21
SEQ ID
NO: 23
VL 4E5 CDR-L3
Residues 89-97 of SEQ ID NO.: 21
SEQ ID
NO: 24
or a variable domain set wherein at least one of said 3 CDR is a modified CDR amino acid sequence having a sequence identity of at least 50% to the parent sequence.
4 . The antibody according to claim 3 , wherein said at least two variable domain CDR sets are selected from a group consisting of:
VH 7F9 set & VL 7F9 set; VH 4E5 set & VL 4E5 and VH 11E6 set & VL 11E6 set.
5 . The antibody according to claim 1 , further comprising a human acceptor framework.
6 . The antibody of claim 1 comprising at least one heavy chain variable domain selected from SEQ ID NO: 56 and 57; and/or at least one light chain variable domain selected from SEQ ID NO: 58 and 59.
7 . The antibody according to claim 6 , wherein said binding protein comprises at least one framework mutation selected from the group consisting of:
(heavy chain sequence position): 1, 2, 68, 70, 72, 76, 85, 89, 95 (light chain sequence position): 11, 13, 43, 49, 58, 70, 87.
8 . The antibody of claim 1 , wherein said binding protein comprises at least one (framework mutated) variable domain having an amino acid sequence selected from the group consisting of:
(heavy chain sequences) SEQ ID NO: 62, 67, 68 and 69; (light chain sequences) SEQ ID NO: 63, 64, 65 and 66.
9 . The antibody of claim 1 , which is selected from the group consisting of antibodies 11E6, 4E5 and 7F9.
10 . An isolated nucleic acid encoding amino acid sequence of the antibody claim 1 .
11 . A vector comprising an isolated nucleic acid according to claim 10 .
12 . A host cell comprising a vector according to claim 11 .
13 . A method of producing a protein capable of binding RAGE, comprising culturing a host cell according to claim 12 in culture medium under conditions sufficient to produce a binding protein capable of binding RAGE.
14 . A protein produced according to the method of 13.
15 . A composition for the release of an antibody said composition comprising
(a) a formulation, wherein said formulation comprises the antibody of claim 1 in crystallized form as an ingredient; and (b) at least one polymeric carrier.
16 . A pharmaceutical composition comprising the antibody of claim 1 , and a pharmaceutically acceptable carrier.
17 . A method for treating a mammal comprising the step of administering to the mammal an effective amount of the composition according to claim 15 .
18 . The method of claim 17 , wherein the method is for treating neurological diseases selected from the group comprising Amytropic Lateral Sclerosis, Brachial Plexus Injury, Brain Injury, including traumatic brain injury, Cerebral Palsy, Friedrich's Ataxia, Guillain Barre, Leukodystrophies, Multiple Sclerosis, Post Polio, Spina Bifida, Spinal Cord Injury, Spinal Muscle Atrophy, Spinal Tumors, Stroke, Transverse Myelitits, dementia, senile dementia, mild cognitive impairment, Alzheimer-related dementia, Huntington's chorea, tardive dyskinesia, hyperkinesias, manias, Morbus Parkinson, steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve trauma, vascular amyloidosis, cerebral hemorrhage I with amyloidosis, brain inflammation, Friedrich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis, glaucoma, Alzheimer's disease, diabetic nephropathy, sepsis, rheumatoid arthritis and related inflammatory diseases.
19 . The method of claim 17 , wherein the method is for treating Alzheimer's disease.
20 . The method of claim 19 , wherein the composition comprises 11E6.Cited by (0)
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