US2018162933A1PendingUtilityA1
Antibodies against the rgm a protein and uses thereof
Est. expiryFeb 29, 2028(~1.6 yrs left)· nominal 20-yr term from priority
A61P 9/10A61P 9/00A61P 7/04A61P 35/00A61P 43/00A61P 25/28A61P 25/18A61P 25/20A61P 25/00A61P 25/02A61P 27/06A61P 25/14A61P 25/16A61P 21/00A61P 21/04C07K 2317/92C07K 2317/565C07K 16/28A61K 45/06C07K 2317/24A61K 39/395C07K 16/22C07K 2317/56A61K 2039/505A61K 39/39533C12N 15/1138C07K 2317/567C07K 2317/76A61K 39/3955Y02A50/30
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Claims
Abstract
The subject invention relates to isolated proteins, particularly monoclonal antibodies, which bind and neutralize RGM A protein. Specifically, these antibodies have the ability to inhibit the binding of RGM A to its receptor and/or coreceptors. These antibodies or portions thereof of the invention are useful for detecting RGM A and for inhibiting RGM A activity, for example in a human suffering from a disorder including but nor limited to multiple sclerosis, mammalian brain trauma, spinal cord injury, stroke, neurodegenerative diseases, and schizophrenia.
Claims
exact text as granted — not AI-modified1 . A binding protein that dissociates from human RGM A with a K D of 1×10 −7 M or less and a k off rate constant of 1×10 −2 s −4 or less, both determined by surface plasmon resonance.
2 . The binding protein of claim 1 that binds to human RGM A and neutralizes the neurite outgrowth inhibitory activity of human RGM A as determined in a standard in vitro assay.
3 . The binding protein of claim 2 , having at least one of the following additional functional characteristics:
binding to rat RGM A, binding to human RGM C, and binding to rat RGM C.
4 . The binding protein of claim 3 , wherein said binding protein modulates the ability of RGM to bind to at least one of its receptors.
5 . The binding protein of claim 4 , wherein said binding protein interacts with a receptor binding domain of human RGM A.
6 . The binding protein of claim 4 , wherein said binding protein modulates at least one of the following interactions:
binding of human RGM A to human BMP-4. binding of hRGM A to human Neogenin, binding of hRGM C to human Neogenin, binding of human RGM A to human BMP-2.
7 . The binding protein according to claim 6 , which is a humanized antibody.
8 . The binding protein according to claim 1 , comprising an antigen binding domain, said binding protein capable of binding an epitope of an RGM molecule, said antigen binding domain comprising at least one CDR comprising an amino acid sequence selected from the group consisting of
(SEQ ID NO: 59)
GTTPDY,
(SEQ ID NO: 62)
FQATHDPLT,
(SEQ ID NO: 65)
ARRNEYYGSSFFDY,
(SEQ ID NO: 68)
LQGYIPPRT,
and
modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.
9 . A binding protein comprising an antigen binding domain, said binding protein capable of binding an epitope of an RGM molecule, said antigen binding domain comprising at least one CDR comprising an amino acid sequence selected from the group consisting of:
(SEQ ID NO: 59)
GTTPDY,
(SEQ ID NO: 62)
FQATHDPLT,
(SEQ ID NO: 65)
ARRNEYYGSSFFDY,
(SEQ ID NO: 68)
LQGYIPPRT,
and
modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.
10 . The binding protein according to claim 9 , further comprising at least one CDR comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 57, 58, 60, 61, 63, 64, 66, 67 and modified CDR amino acid sequences having a sequence identity of at least 50% to one of said sequences.
11 . The binding protein according to claim 1 , wherein said at least one CDR comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO: 57
Residues 31-35 of SEQ ID NO.: 34
SEQ ID NO: 58
Residues 50-66 of SEQ ID NO.: 34
SEQ ID NO: 59
Residues 99-104 of SEQ ID NO.: 34
SEQ ID NO: 60
Residues 24-39 of SEQ ID NO.: 10
SEQ ID NO: 61
Residues 55-61 of SEQ ID NO.: 10
SEQ ID NO: 62
Residues 94-102 of SEQ ID NO.: 10
SEQ ID NO: 63
Residues 31-35 of SEQ ID NO.: 55
SEQ ID NO: 64
Residues 50-66 of SEQ ID NO.: 55
SEQ ID NO: 65
Residues 97-110 of SEQ ID NO.: 55
SEQ ID NO: 66
Residues 24-34 of SEQ ID NO.: 56
SEQ ID NO: 67
Residues 50-56 of SEQ ID NO.: 56
SEQ ID NO: 68
Residues 89-97 of SEQ ID NO.: 56
12 . The binding protein according to claim 11 , comprising at least 3 CDRs which are selected from a variable domain CDR set consisting of:
VH 5F9 set
VH 5F9 CDR-H1
Residues 31-35 of SEQ ID NO.: 34
SEQ ID NO: 57
VH 5F9 CDR-H2
Residues 50-66 of SEQ ID NO.: 34
SEQ ID NO: 58
VH 5F9 CDR-H3
Residues 99-104 of SEQ ID NO.: 34
SEQ ID NO: 59
VL 5F9 set
VL 5F9 CDR-L1
Residues 24-39 of SEQ ID NO.: 10
SEQ ID NO: 60
VL 5F9 CDR-L2
Residues 55-61 of SEQ ID NO.: 10
SEQ ID NO: 61
VL 5F9 CDR-L3
Residues 94-102 of SEQ ID NO.: 10
SEQ ID NO: 62
VH 8D1 set
VH 8D1 CDR-H1
Residues 31-35 of SEQ ID NO.: 55
SEQ ID NO: 63
VH 8D1 CDR-H2
Residues 50-66 of SEQ ID NO.: 55
SEQ ID NO: 64
VH 8D1 CDR-H3
Residues 97-110 of SEQ ID NO.: 55
SEQ ID NO: 65
VL 8D1 set
VL 8D1 CDR-L1
Residues 24-34 of SEQ ID NO.: 56
SEQ ID NO: 66
VL 8D1 CDR-L2
Residues 50-56 of SEQ ID NO.: 56
SEQ ID NO: 67
VL 8D1 CDR-L3
Residues 89-97 of SEQ ID NO.: 57
SEQ ID NO: 68
or a variable domain set wherein at least one of said 3 CDRs is a modified CDR amino acid sequence having a sequence identity of at least 50% to the parent sequence.
13 . The binding protein according to claim 12 , comprising at least two variable domain CDR sets.
14 . The binding protein according to claim 13 , wherein said at least two variable domain CDR sets are selected from a group consisting of:
VH 5F9 set & VL 5F9 set; and VH 8D1 set & VL 8D1 set
15 . The binding protein according to claim 14 , further comprising a human acceptor framework.
16 . The binding protein according to claim 15 , wherein said human acceptor framework comprises at least one amino acid sequence selected from the group consisting of SEQ ID NO: 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and 33.
17 . The binding protein according to claim 16 , comprising a set of framework sequences selected from the group consisting of the sets:
VH3-48 set (Seq ID NO: 15, 16 and 17) VH3-33 set (SEQ ID NO: 21, 22 and 23) VH3-23 set (SEQ ID NO: 24, 25 and 26)
each of which sets being combined with a further framework sequence, selected from
JH3 (SEQ ID NO:18),
JH4 (SEQ ID NO:19),
JH6 (SEQ ID NO:20);
or selected from the group consisting of the sets A18 set: (SEQ ID NO: 27, 28 and 29) A17 set: (SEQ ID NO: 31, 32 and 33)
each of which sets being combined with a further framework sequence, selected from JK2 (SEQ ID NO:2)
18 . The binding protein of claim 16 , comprising at least one heavy chain variable domain selected from SEQ ID NO: 35, 36, 37, 38, 39, 40, 41, 42, and 43; and/or at least one light chain variable domain selected from SEQ ID NO: 44, 45, and 46.
19 . The binding protein of claim 18 , wherein said binding protein comprises two variable domains, wherein said two variable domains have amino acid sequences selected from:
SEQ ID NOs: 35 & 44; 36 & 44; 37 & 44; 38 & 44; 39 & 44; 40 & 44; 41 & 44; 42 & 44; 43 & 44; SEQ ID NOs: 35 & 45; 36 & 45; 37 & 45; 38 & 45; 39 & 45; 40 & 45; 41 & 45; 42 & 45; 43 & 45; SEQ ID NOs: 35 & 46; 36 & 46; 37 & 46; 38 & 46; 39 & 46; 40 & 46; 41 & 46; 42 & 46; 43 & 46;
20 . The binding protein according to claim 15 , wherein said human acceptor framework comprises at least one framework region amino acid substitution at a key residue, said key residue selected from the group consisting of:
a residue adjacent to a CDR; a glycosylation site residue; a rare residue; a residue capable of interacting with a RGM epitope; a residue capable of interacting with a CDR; a canonical residue; a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone; an N-terminal residue capable of paraglutamate formation; and a residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 and a Kabat-defined first heavy chain framework.
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