US2014127209A1PendingUtilityA1
Antibody derivatives
Est. expirySep 10, 2030(~4.2 yrs left)· nominal 20-yr term from priority
Inventors:Kenneth H. GrabsteinWilliam BradyGordon KingNatalie Winblade NairnKurt ShanebeckPaul Heffner SlagleKenneth Christopher ThorntonMichael Peter VanbruntAndrea WangHengyu Xu
A61P 43/00A61P 3/10A61P 37/06A61P 37/02A61P 25/00A61P 29/00C07K 2317/56C07K 2317/33C07K 2317/76C07K 2317/622C07K 2317/92C07K 16/244C07K 2317/24C07K 16/248A61P 17/06A61P 1/00C07K 2317/31C07K 2317/40A61K 2039/505C07K 2317/567A61P 19/02C07K 2317/565C07K 16/468A61K 2039/507
38
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Claims
Abstract
The invention relates inter alia to a bivalent, bispecific construct comprising an anti-IL-6 antibody, or derivative thereof, and an anti-IL-23 antibody, or derivative thereof and its use in therapy. The invention also relates to useful anti-IL-6 antibodies and anti-IL-23 antibodies.
Claims
exact text as granted — not AI-modified1 . A bivalent, bispecific construct comprising an anti-IL-6 antibody, or derivative thereof, and an anti-IL-23 antibody, or derivative thereof.
2 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, is, or is derived from, a monoclonal antibody and/or the anti-IL-23 antibody, or derivative thereof, is, or is derived from, a monoclonal antibody.
3 . A bivalent, bispecific construct according to claim 2 , wherein the monoclonal antibodies are human, chimeric or humanized monoclonal antibodies.
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9 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, comprises a CDR2 region comprising the amino acid sequence YIYTDX 1 STX 2 YANWAKG (SEQ ID NO. 335), wherein
X 1 is selected from the group consisting of glycine, asparagine, glutamine, cysteine, serine, threonine, and tyrosine; and X 2 is selected from the group consisting of phenylalanine, tryptophan, and tyrosine; wherein the anti-IL-6, or derivative thereof, comprises a CDR5 region comprising the amino acid sequence RX 1 STLX 2 S, wherein X 1 and X 2 are independently alanine and threonine.
10 . (canceled)
11 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, comprises at least one CDR region whose amino acid sequence is selected from the group consisting of SEQ ID NOs. 10-15.
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14 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, comprises the amino acid sequences of SEQ ID NO.s 10-15.
15 . A bivalent, bispecific construct according to claim 1 , wherein the heavy chain of the anti-IL-6 antibody, or derivative thereof, comprises SEQ ID NO. 259 or SEQ ID NO. 261.
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17 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, is a scFv and wherein the anti-IL-23 antibody, or derivative thereof, is a scFv.
18 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, is a scFv comprising
(i) a heavy chain comprising at least one CDR having a sequence selected from the group consisting of SEQ ID NOs. 10-12; and (ii) a light chain comprising at least one CDR having a sequence selected from the group consisting of SEQ ID NOs. 13-15.
19 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, is a scFv comprising
(i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 259; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 261.
20 . (canceled)
21 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, comprises at least one CDR region whose amino acid sequence comprises one or more amino acid additions, deletions or substitutions to an amino acid sequence selected from the group consisting of SEQ ID NO.s 10-15 or wherein the anti-IL-6 antibody, or derivative thereof, comprises at least one CDR region whose amino acid sequence comprises one or more conservative amino acid substitutions to an amino acid sequence selected from the group consisting of SEQ ID NO.s 10-15.
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23 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, comprises at least one CDR region that binds to the same epitope as an anti-IL-6 antibody having CDRs corresponding to the amino acid sequences of SEQ ID NOs. 10-15.
24 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, is selected from, or derived from, the group consisting of 13A8, 9H4, 9C8, 8C8, 18D4, and 28D2.
25 . A bivalent, bispecific construct according to claim 1 wherein the anti-IL-23 antibody, or derivative thereof, comprises a CDR2 region comprising the amino acid sequence YYAX 1 WAX 2 G (SEQ ID NO. 337), wherein
X 1 is selected from the group consisting of serine, proline and aspartate, and
X 2 is selected from the group consisting of lysine and glutamine
or wherein the anti-IL-23 antibody, or derivative thereof, comprises a CDR5 region comprising the amino acid sequence AX 1 TLX 2 S (SEQ ID NO. 338), wherein
X 1 is selected from the group consisting of serine and alanine
X 2 is selected from the group consisting of alanine and threonine.
26 . (canceled)
27 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-23 antibody, or derivative thereof, comprises at least one CDR region whose amino acid sequence is selected from the group consisting of SEQ ID NOs. 90-95.
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30 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-6 antibody, or derivative thereof, comprises the amino acid sequences of SEQ ID NOs. 90-95.
31 . A bivalent, bispecific construct according to claim 1 , wherein the heavy chain of the anti-IL-23 antibody, or derivative thereof, comprises SEQ ID NO. 267 or SEQ ID NO. 269.
32 . (canceled)
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34 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-23 antibody, or derivative thereof, is a scFv comprising
(i) a heavy chain comprising at least one CDR having a sequence selected from the group consisting of SEQ ID NOs. 90-92; and (ii) a light chain comprising at least one CDR having a sequence selected from the group consisting of SEQ ID NOs. 93-95.
35 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-23 antibody, or derivative thereof, is a scFv comprising
(i) a heavy chain comprising SEQ ID NO. 267; and (ii) a light chain comprising SEQ ID NO. 269.
36 . (canceled)
37 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-23 antibody, or derivative thereof, comprises at least one CDR region whose amino acid sequence comprises one or more amino acid additions, deletions or substitutions to an amino acid sequence selected from the group consisting of SEQ ID NOs. 90-95 or wherein the anti-IL-23 antibody, or derivative thereof, comprises at least one CDR region whose amino acid sequence comprises one or more conservative amino acid substitutions to an amino acid sequence selected from the group consisting of SEQ ID NOs. 90-95.
38 . (canceled)
39 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-23 antibody, or derivative thereof, comprises at least one CDR region that binds to the same epitope as an anti-IL-23 antibody having CDRs corresponding to the amino acid sequences of SEQ ID NOs. 90-95.
40 . A bivalent, bispecific construct according to claim 1 , wherein the anti-IL-23 antibody, or derivative thereof, is selected from, or derived from, the group consisting of 31A12, 34E11, 35H4, 49B7 and 16C6.
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62 . A bivalent, bispecific construct according to claim 1 wherein both the anti-IL-6 antibody, or derivative thereof, and the anti-IL-23 antibody, or derivative thereof, incorporate one or more non-natural amino acids.
63 . A bivalent, bispecific construct according to claim 62 wherein the anti-IL-6 antibody, or derivative thereof, is coupled to the anti-IL-23 antibody, or derivative thereof, through a linker between a non-natural amino acid in each antibody, or derivative thereof.
64 . A bivalent, bispecific construct according to claim 63 , wherein linker comprises a PEG molecule.
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89 . A method for producing a bivalent, bispecific construct according to claim 1 comprising:
(i) providing an anti-IL-6 antibody, or derivative thereof which is modified by incorporation at least one non-natural amino acid;
(ii) providing an anti-IL-23 antibody, or derivative thereof (including an anti-IL-23/IL-12 antibody or derivative thereof), which is modified by incorporation of at least one non-natural amino acid;
(iii) reacting the modified anti-IL-6 antibody, or modified derivative thereof, with the modified anti-IL-23 antibody, or modified derivative thereof, such that the two are coupled through a linkage between a non-natural amino acid of each portion.
90 . A method according to claim 89 , wherein the linkage between modified anti-IL-6 antibody, or modified derivative thereof, and the modified anti-IL-23 antibody, or modified derivative thereof, comprises a linker portion, wherein one end of the linker portion is coupled to a non-natural amino acid of the modified anti-IL-6 antibody, or modified derivative thereof, and the other end of the linker portion is coupled to a non-natural amino acid of the modified anti-IL-23 antibody, or modified derivative thereof.
91 . A method according to claim 90 , wherein the linker portion comprises PEG, a water soluble polymer, polyvinylalcohol, a polysaccharide, a polyalkylene oxide, hydroxyethyl starch, or a polyol.
92 . A method according to claim 89 , wherein the non-natural amino acid contains an azide, alkyne, alkene, strained cyclooctyne, strained cycloalkene, cyclopropene, norbornenes or aryl, alkyl or vinyl halide, ketone, aldehyde, cyano, hydrazine, ketals, acetals, hydrazide, alkoxy amine, boronic acid, organotin, organosilicon, beta-silyl alkenyl halide, beta-silyl alkenyl sulfonates, nitrile oxides, pyrones, tetrazine, pyridazine, aryl sulfonates, thiosemicarbazide, semicarbazide, tetrazole, alpha-ketoacid group prior to linkage.
93 . A method according to claim 89 , wherein the non-natural amino acid is azidohomoalanine, homopropargylglycine, homoallylglycine, p-bromophenylalanine, p-iodophenylalanine, azidophenylalanine, acetylphenylalanine or ethynylephenylalanine, amino acids containing an internal alkene such as trans-crotylalkene, serine allyl ether, allyl glycine, propargyl glycine, or vinyl glycine, pyrrolysine, N-sigma-o-azidobenzyloxycarbonyl-L-Lysine (AzZLys), N-sigma-propargyloxycarbonyl-L-Lysine, N-sigma-2-azidoethoxycarbonyl-L-Lysine, N-sigma-tert-butyloxycarbonyl-L-Lysine (BocLys), N-sigma-allyloxycarbonyl-L-Lysine (AlocLys), N-sigma-acetyl-L-Lysine (AcLys), N-sigma-benzyloxycarbonyl-L-Lysine (ZLys), N-sigma-cyclopentyloxycarbonyl-L-Lysine (CycLys), N-sigma-D-prolyl-L-Lysine, N-sigma-nicotinoyl-L-Lysine (NicLys), N-sigma-N-Me-anthraniloyl-L-Lysine (NmaLys), N-sigma-biotinyl-L-Lysine, N-sigma-9-fluorenylmethoxycarbonyl-L-Lysine, N-sigma-methyl-L-Lysine, N-sigma-dimethyl-L-Lysine, N-sigma-trimethyl-L-Lysine, N-sigma-isopropyl-L-Lysine, N-sigma-dansyl-L-Lysine, N-sigma-o,p-dinitrophenyl-L-Lysine, N-sigma-p-toluenesulfonyl-L-Lysine, N-sigma-DL-2-amino-2-carboxyethyl-L-Lysine, N-sigma-phenylpyruvamide-L-Lysine, N-sigma-pyruvamide-L-Lysine.
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98 . A method of treating T H 17, T H 22 or T H 1 mediated diseases comprising the step of administering a therapeutically effective amount of a bivalent bispecific construct according to claim 1 to a patient.
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