US2020148780A1PendingUtilityA1
Cd 14 antagonist antibodies for treating neurodegenerative diseases
Assignee: Implicit Bioscience Pty LtdPriority: Apr 21, 2017Filed: Apr 20, 2018Published: May 14, 2020
Est. expiryApr 21, 2037(~10.7 yrs left)· nominal 20-yr term from priority
Inventors:Garry L. Redlich
C07K 2317/565A61K 45/06C07K 2317/24C07K 16/2896C07K 2317/70C07K 2317/51C07K 2317/515A61P 25/02A61K 38/00A61P 25/28A61K 2039/505A61K 2039/545
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Claims
Abstract
This invention relates generally to agents and methods for treating the development or progression of a neurodegenerative disease. In particular, the present invention relates to CD14 antagonists for use in treating the development or progression of a neurodegenerative disease, including Motor Neurone Disease (MND) and Dementia disease or associated symptoms. The present invention further provides compositions including such agents.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of inhibiting or decreasing the production of a pro-inflammatory mediator from a mammalian cell in the periphery of a subject with a neurodegenerative disease, comprising, consisting or consisting essentially of contacting membrane bound CD14 (mCD14) or soluble CD14 (sCD14) with a CD14 antagonist antibody in an amount sufficient to inhibit or decrease the production of a pro-inflammatory mediator from a peripheral cell.
2 . A method for treating the development or progression of a neurodegenerative disease or a symptom thereof in a subject, the method comprising, consisting or consisting essentially of administering systemically an effective amount of a CD14 antagonist antibody to the subject.
3 . Use of a CD14 antagonist antibody for treating the development or progression of a neurodegenerative disease, wherein the CD14 antagonist antibody is administered systemically.
4 . The use according to claim 3 , wherein the CD14 antagonist antibody is manufactured as a medicament for the said application.
5 . The method or use according to any one of claims 2 to 4 , wherein the CD14 antagonist antibody inhibits or decreases the production of one or more pro-inflammatory mediators by a peripheral cell in the subject.
6 . The method or use according to claim 5 , wherein the CD14 antagonist antibody binds to both mCD14 and sCD14.
7 . The method or use according to claim 1 , claim 5 or claim 6 , wherein the peripheral cell is an immune cell.
8 . The method or use according to claim 7 , wherein the immune cell is selected from a monocyte, macrophage, dendritic cell or T-cell.
9 . The method or use according to any one of claims 1 to 8 , wherein the pro-inflammatory mediator is a cytokine selected from one or more of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1)-α, IL-6, IFN-γ, IFN-β, IL-1β, IL-8, IL-17 and IL-18.
10 . The method or use according to any one of claims 1 to 9 , further comprising identifying that the subject has or is at risk of developing a neurodegenerative disease, suitably prior to administration of the CD14 antagonist antibody.
11 . The method or use according to any one of claims 1 to 10 , wherein the neurodegenerative disease or disorder is selected from an MND or dementia.
12 . The method or use of claim 11 , wherein the MND is selected from the group consisting of amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), progressive bulbar palsy (PBP), pseudobulbar palsy.
13 . The method or use according to claim 12 , wherein the MND is ALS.
14 . The method or use according to claim 11 , wherein the Dementia is selected from the group consisting of Alzheimer's disease, a Lewy body dementia, Frontotemporal Dementia (FTD) and Vascular Dementia.
15 . The method or use according to anyone of claims 1 to 14 , wherein the CD14 antagonist antibody is selected from:
(1) an antibody comprising:
a VL domain that comprises, consists or consists essentially of the sequence:
(3C10 VL)
[SEQ ID NO: 1]
QSPASLAVSLGQRATISCRASESVDSFGNSFMHWYQQKAGQPPKSSIY
RAANLESGIPARFSGSGSRTDFTLTINPVEADDVATYFCQQSYEDPWT
FGGGTKLGNQ;
and
a VH domain that comprises, consists or consists essentially of the sequence:
(3C10 VH)
[SEQ ID NO: 2]
LVKPGGSLKLSCVASGFTFSSYAMSWVRQTPEKRLEWVASISSGGTT
YYPDNVKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYYDYHY
WGQGTTLTVSS;
(2) an antibody comprising:
a VL domain that comprises, consists or consists essentially of the sequence:
(28C5 VL)
[SEQ ID NO: 3]
QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLI
YRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYCCQQSNEDP
TTFGGGTKLEIK;
and
a VH domain that comprises, consists or consists essentially of the sequence:
(28C5 VH)
[SEQ ID NO: 4]
LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMG
YISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCV
RGLRFAYWGQGTLVTVSA;
and
(3) an antibody comprising:
a VL domain that comprises, consists or consists essentially of the sequence:
(18E12 VL)
[SEQ ID NO: 5]
QTPSSLSASLGDRVTISCRASQDIKNYLNWYQQPGGTVKVLIYYTSR
LHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQRGDTLPWTFGG
GTKLEIK;
and
a VH domain that comprises, consists or consists essentially of the sequence:
(18E12 VH)
[SEQ ID NO: 6]
LESGPGLVAPSQSLSITCTVSGFSLTNYDISWIRQPPGKGLEWLGVI
WTSGGTNYNSAFMSRLSITKDNSESQVFLKMNGLQTDDTGIYYCVRG
DGNFYLYNFDYWGQGTTLTVSS.
16 . The method or use according to claim 15 , wherein the CD14 antagonist antibody comprises, consists or consists essentially of the VL and VH CDR sequences of the above antibodies defined in claim 13 .
17 . The method or use according to claim 16 , wherein the CD14 antagonist antibody is selected from:
(1) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSFGNSFMH [SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 comprises the sequence RAANLES [SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 comprises the sequence QQSYEDPWT [SEQ ID NO: 9] (3C10 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3); (2) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3); and (3) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence NYDIS [SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 comprises the sequence VIWTSGGTNYNSAFMS [SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 comprises the sequence GDGNFYLYNFDY [SEQ ID NO: 24] (18E12 H-CDR3).
18 . The method or use according to claim 17 , wherein the CD14 antagonist antibody is humanized.
19 . The method or use according to claim 18 , wherein the CD14 antagonist antibody comprises a VL domain and a VH domain, wherein:
the VL domain comprises the amino acid sequence:
[SEQ ID NO: 25]
METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCRASE
SVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTD
FTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFI
FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT
EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR
GEC;
and
the VH domain comprises the amino acid sequence:
[SEQ ID NO: 26]
MKVLSLLYLLTAIPGILSDVQLQQSGPGLVKPSQSLSLTCTVTGYSI
TSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSK
NQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTKGPSV
FPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY
GPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE
DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV
SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL
TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK.
20 . The method or use according to claim 19 , wherein the CD14 antagonist antibody is IC14, or an antigen-binding fragment thereof.
21 . The method or use according to any one of claims 1 to 20 , wherein the CD14 antagonist is administered in combination with one or more ancillary anti-neurodegenerative agents that treat the neurodegenerative disease or the symptoms thereof.
22 . The method or use according to claim 21 , wherein the CD14 antagonist antibody and the ancillary anti-neurodegenerative agent are administered in synergistically effective amounts.
23 . The method or use according to claim 22 , wherein the CD14 antagonist antibody and the ancillary anti-neurodegenerative agent are administered simultaneously or sequentially.
24 . The method or use according to claim 23 , wherein the ancillary anti-neurodegenerative agent is an anti-inflammatory.
25 . The method or use according to claim 24 , wherein the anti-inflammatory is a complement pathway inhibitor.
26 . The method or use according to claim 25 , wherein the complement pathway inhibitor is a C5a inhibitor.
27 . The method or use according to claim 26 , wherein the C5a inhibitor is PMX205 or eculizumab.
28 . The method or use according to claim 23 , wherein the ancillary anti-neurodegenerative agent is an agent that blocks the interaction between CD40 and CD40 ligand.
29 . The method or use according to claim 28 , wherein the agent is an antibody that bind specifically to CD40 and/or CD40 ligand.
30 . The method or use according to claim 29 , wherein the antibody is AT-1502.
31 . The method of use according to claim 20 , wherein the ancillary anti-neurodegenerative agent is riluzole or edaravone.
32 . A pharmaceutical composition for treating the progression or development of a neurodegenerative disease, or a symptom thereof, comprising, consisting or consisting essentially of a CD14 antagonist antibody, together with a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated for systemic administration.
33 . The pharmaceutical composition according to claim 32 , wherein the CD14 antagonist antibody binds to both sCD14 and mCD14 and inhibits or decreases the production of one or more pro-inflammatory mediators by a peripheral cell in the subject.
34 . The pharmaceutical composition according to claim 33 , wherein the cell is an immune cell.
35 . The pharmaceutical composition according to claim 34 , wherein the immune cell is selected from a monocyte, macrophage, dendritic cell or T cell.
36 . The pharmaceutical composition according to any one of claims 32 to 35 , wherein the pro-inflammatory mediator is a cytokine selected from one or more of tumor necrosis factor-α(TNF-α), interleukin-1 (IL-1)-α, IL-6, IFN-γ, IFN-β, IL-1β, IL-8, IL-17 and IL-18.
37 . The pharmaceutical composition according to any one of claims 32 to 36 , further comprising identifying that the subject has or is at risk of developing a neurodegenerative disease, suitably prior to administration of the CD14 antagonist antibody.
38 . The pharmaceutical composition according to any one of claims 32 to 37 , wherein the neurodegenerative disease or disorder is selected from a MND or Dementia.
39 . The pharmaceutical composition of claim 38 , wherein the MND is selected from the group consisting of amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), progressive bulbar palsy (PBP), pseudobulbar palsy.
40 . The pharmaceutical composition according to claim 38 , wherein the MND is ALS.
41 . The pharmaceutical composition according to claim 38 , wherein the dementia is selected from the group consisting of Alzheimer's disease, a Lewy body dementia, Frontotemporal Dementia (FTD) and Vascular Dementia.
42 . The pharmaceutical composition according to anyone of claims 32 to 41 , wherein the CD14 antagonist antibody is selected from:
(1) an antibody comprising:
a VL domain that comprises, consists or consists essentially of the sequence:
(3C10 VL)
[SEQ ID NO: 1]
QSPASLAVSLGQRATISCRASESVDSFGNSFMHWYQQKAGQPPKSSI
YRAANLESGIPARFSGSGSRTDFTLTINPVEADDVATYFCQQSYEDP
WTFGGGTKLGNQ;
and
a VH domain that comprises, consists or consists essentially of the sequence:
(3C10 VH)
[SEQ ID NO: 2]
LVKPGGSLKLSCVASGFTFSSYAMSWVRQTPEKRLEWVASISSGGTT
YYPDNVKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYYDYHY
WGQGTTLTVSS;
(2) an antibody comprising:
a VL domain that comprises, consists or consists essentially of the sequence:
(28C5 VL)
[SEQ ID NO: 3]
QSPASLAVSLGQRATISCRASESVDSYVNSFLHWYQQKPGQPPKLLI
YRASNLQSGIPARFSGSGSRTDFTLTINPVEADDVATYCCQQSNEDP
TTFGGGTKLEIK;
and
a VH domain that comprises, consists or consists essentially of the sequence:
(28C5 VH)
[SEQ ID NO: 4]
LQQSGPGLVKPSQSLSLTCTVTGYSITSDSAWNWIRQFPGNRLEWMG
YISYSGSTSYNPSLKSRISITRDTSKNQFFLQLNSVTTEDTATYYCV
RGLRFAYWGQGTLVTVSA;
and
(3) an antibody comprising:
a VL domain that comprises, consists or consists essentially of the sequence:
(18E12 VL)
[SEQ ID NO: 5]
QTPSSLSASLGDRVTISCRASQDIKNYLNWYQQPGGTVKVLIYYTSR
LHSGVPSRFSGSGSGTDYSLTISNLEQEDFATYFCQRGDTLPWTFGG
GTKLEIK;
and
a VH domain that comprises, consists or consists essentially of the sequence:
(18E12 VH)
[SEQ ID NO: 6]
LESGPGLVAPSQSLSITCTVSGFSLTNYDISWIRQPPGKGLEWLGVI
WTSGGTNYNSAFMSRLSITKDNSESQVFLKMNGLQTDDTGIYYCVRG
DGNFYLYNFDYWGQGTTLTVSS.
43 . The pharmaceutical composition according to claim 42 , wherein the CD14 antagonist antibody comprises, consists or consists essentially of the VL and VH CDR sequences of the above antibodies defined in claim 10 .
44 . The pharmaceutical composition according to claim 43 , wherein the CD14 antagonist antibody is selected from:
(1) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSFGNSFMH [SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 comprises the sequence RAANLES [SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 comprises the sequence QQSYEDPWT [SEQ ID NO: 9] (3C10 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises the sequence SISSGGTTYYPDNVKG [SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises the sequence GYYDYHY [SEQ ID NO: 12] (3C10 H-CDR3); (2) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASESVDSYVNSFLH [SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises the sequence RASNLQS [SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises the sequence QQSNEDPTT [SEQ ID NO: 15] (28C5 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises the sequence YISYSGSTSYNPSLKS [SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3); and (3) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence RASQDIKNYLN [SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises the sequence YTSRLHS [SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises the sequence QRGDTLPWT [SEQ ID NO: 21] (18E12 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence NYDIS [SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 comprises the sequence VIWTSGGTNYNSAFMS [SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 comprises the sequence GDGNFYLYNFDY [SEQ ID NO: 24] (18E12 H-CDR3).
45 . The pharmaceutical composition according to claim 44 , wherein the CD14 antagonist antibody is humanized.
46 . The pharmaceutical composition according to claim 45 , wherein the CD14 antagonist antibody comprises a VL domain and a VH domain, wherein:
the VL domain comprises the amino acid sequence:
[SEQ ID NO: 25]
METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCRASE
SVDSYVNSFLHWYQQKPGQPPKLLIYRASNLQSGIPARFSGSGSRTD
FTLTINPVEADDVATYYCQQSNEDPYTFGGGTKLEIKRTVAAPSVFI
FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT
EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR
GEC;
and
the VH domain comprises the amino acid sequence:
[SEQ ID NO: 26]
MKVLSLLYLLTAIPGILSDVQLQQSGPGLVKPSQSLSLTCTVTGYSI
TSDSAWNWIRQFPGNRLEWMGYISYSGSTSYNPSLKSRISITRDTSK
NQFFLQLNSVTTEDTATYYCVRGLRFAYWGQGTLVTVSSASTKGPSV
FPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKY
GPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQE
DPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV
SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL
TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK.
47 . The pharmaceutical composition according to claim 46 , wherein the CD14 antagonist antibody is IC14, or an antigen-binding fragment thereof.
48 . The pharmaceutical composition according to any one of claims 31 to 46 , wherein the pharmaceutical composition further comprises an ancillary anti-neurodegenerative agent, wherein the ancillary agent treats the disease or symptoms thereof.
49 . The pharmaceutical composition according to claim 48 , wherein the ancillary anti-neurodegenerative agent is an anti-inflammatory.
50 . The pharmaceutical composition according to claim 49 , wherein the anti-inflammatory is a complement inhibitor.
51 . The pharmaceutical composition according to claim 50 , wherein the complement inhibitor is a C5a inhibitor.
52 . The pharmaceutical composition according to claim 51 , wherein the C5a inhibitor is PMX205 or eculizumab.
53 . The pharmaceutical composition according to claim 48 , wherein the ancillary anti-neurodegenerative agent is an agent that blocks the interaction between CD40 and CD40 ligand.
54 . The pharmaceutical composition according to claim 53 , wherein the agent is an antibody that bind specifically to CD40 and/or CD40 ligand.
55 . The pharmaceutical composition according to claim 54 , wherein the antibody is AT-1502.
56 . The pharmaceutical composition according to claim 48 , wherein the ancillary anti-neurodegenerative agent is riluzole or edaravone.Join the waitlist — get patent alerts
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