NZ807887A - Antibodies to feline mcdonough sarcoma (fms)-like tyrosine kinase 3 receptor ligand (flt3l) and uses thereof for treating autoimmune and inflammatory diseases - Google Patents
Antibodies to feline mcdonough sarcoma (fms)-like tyrosine kinase 3 receptor ligand (flt3l) and uses thereof for treating autoimmune and inflammatory diseasesInfo
- Publication number
- NZ807887A NZ807887A NZ807887A NZ80788719A NZ807887A NZ 807887 A NZ807887 A NZ 807887A NZ 807887 A NZ807887 A NZ 807887A NZ 80788719 A NZ80788719 A NZ 80788719A NZ 807887 A NZ807887 A NZ 807887A
- Authority
- NZ
- New Zealand
- Prior art keywords
- antibody
- antigen
- binding fragment
- seq
- constant domain
- Prior art date
Links
- 230000001363 autoimmune Effects 0.000 title abstract 2
- 208000027866 inflammatory disease Diseases 0.000 title abstract 2
- 208000023275 Autoimmune disease Diseases 0.000 title 1
- 241000282324 Felis Species 0.000 title 1
- 101001052849 Homo sapiens Tyrosine-protein kinase Fer Proteins 0.000 title 1
- 206010039491 Sarcoma Diseases 0.000 title 1
- 102100024537 Tyrosine-protein kinase Fer Human genes 0.000 title 1
- 239000003446 ligand Substances 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract 16
- 239000012634 fragment Substances 0.000 claims 30
- 239000000427 antigen Substances 0.000 claims 29
- 102000036639 antigens Human genes 0.000 claims 29
- 108091007433 antigens Proteins 0.000 claims 29
- 102100020715 Fms-related tyrosine kinase 3 ligand protein Human genes 0.000 claims 11
- 101710162577 Fms-related tyrosine kinase 3 ligand protein Proteins 0.000 claims 11
- 125000003275 alpha amino acid group Chemical group 0.000 claims 11
- 210000004027 cell Anatomy 0.000 claims 8
- 210000001744 T-lymphocyte Anatomy 0.000 claims 6
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims 5
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims 5
- 102000039446 nucleic acids Human genes 0.000 claims 4
- 108020004707 nucleic acids Proteins 0.000 claims 4
- 150000007523 nucleic acids Chemical class 0.000 claims 4
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 claims 3
- 101000716729 Homo sapiens Kit ligand Proteins 0.000 claims 3
- 102000055151 human KITLG Human genes 0.000 claims 3
- 210000005134 plasmacytoid dendritic cell Anatomy 0.000 claims 3
- 210000002966 serum Anatomy 0.000 claims 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 2
- 108060003951 Immunoglobulin Proteins 0.000 claims 2
- 210000004443 dendritic cell Anatomy 0.000 claims 2
- 102000018358 immunoglobulin Human genes 0.000 claims 2
- 239000012528 membrane Substances 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims 1
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 claims 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims 1
- 201000002481 Myositis Diseases 0.000 claims 1
- 208000034943 Primary Sjögren syndrome Diseases 0.000 claims 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims 1
- 230000004913 activation Effects 0.000 claims 1
- 102000025171 antigen binding proteins Human genes 0.000 claims 1
- 108091000831 antigen binding proteins Proteins 0.000 claims 1
- 210000003719 b-lymphocyte Anatomy 0.000 claims 1
- 210000004899 c-terminal region Anatomy 0.000 claims 1
- 238000012258 culturing Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000012636 effector Substances 0.000 claims 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 claims 1
- 210000004408 hybridoma Anatomy 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 210000000274 microglia Anatomy 0.000 claims 1
- 210000001616 monocyte Anatomy 0.000 claims 1
- 201000008383 nephritis Diseases 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000002243 precursor Substances 0.000 claims 1
- 230000011664 signaling Effects 0.000 claims 1
- 210000000130 stem cell Anatomy 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
Abstract
Provided herein are anti-FLT3L antibodies and methods of using the antibodies to treat autoimmune and other inflammatory diseases.
Claims (29)
1. An antibody or antigen-binding fragment thereof that specifically binds to FLT3L, comprising a set of Complementarity-Determining Regions (CDRs): HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of: (a) SEQ ID NOs: 29, 30, 31, 32, 33, and 34, respectively; or (b) SEQ ID NOs: 29, 30, 31, 35, 33, and 34, respectively; or (c) SEQ ID Nos: 29, 36, 37, 32, 33, and 38, respectively.
2. The antibody or antigen-binding fragment thereof of claim 1, comprising a heavy chain variable region (VH) and light chain variable region (VL), wherein each VH and VL comprises three CDRs and four framework regions (FWs), arranged from amino-terminus to carboxyterminus in the following order: FW1, CDR1, FW2, CDR2, FW3, CDR3, and FW4, wherein the VH and VL regions have and amino acid sequence having at least 95%, 96%, 97%, 98%, or 99% sequence identity to: (a) SEQ ID NO: 1 and SEQ ID NO: 2, respectively; or (b) SEQ ID NO: 3 and SEQ ID NO: 4, respectively; or (c) SEQ ID NO: 5 and SEQ ID NO: 6, respectively; preferably, wherein the CDRs of the VH (HCDR1, HCDR2, and HCDR3) and the CDRs of the VL (LCDR1, LCDR2, and LCDR3) consist of the amino acid sequences of: (a’) SEQ ID NOs: 29, 30, 31, 32, 33, and 34, respectively; or (b’) SEQ ID NOs: 29, 30, 31, 35, 33, and 34, respectively; or (c’) SEQ ID Nos: 29, 36, 37, 32, 33, and 38, respectively.
3. The antibody or antigen-binding fragment thereof of claim 2, wherein the VH and VL comprise the amino acid sequence of: (a) SEQ ID NO: 1 and SEQ ID NO: 2, respectively; or (b) SEQ ID NO: 3 and SEQ ID NO: 4, respectively; or (c) SEQ ID NO: 5 and SEQ ID NO: 6, respectively; preferably comprising: (a’) a heavy chain region having an amino acid sequence comprising SEQ ID NO: 61 and a light chain region having an amino acid sequence comprising SEQ ID NO: 62; or 76 (b’) a heavy chain region having an amino acid sequence comprising SEQ ID NO: 65 and a light chain region having an amino acid sequence comprising SEQ ID NO: 66; or (c’) a heavy chain region having an amino acid sequence comprising SEQ ID NO: 69 and a light chain region having an amino acid sequence comprising SEQ ID NO: 70.
4. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof inhibits FLT3L-mediated activation of membrane bound FLT3 on human stem cells, hematopoietic cell precursors, dendritic cells, activated T and B cells, monocytes, or microglia; preferably wherein the antibody or antigenbinding fragment thereof does not specifically bind to at least one of human stem cell factor (huSCF) and human colony stimulating factor (huCSF1); more preferably, wherein the antibody or antigen-binding fragment thereof does not specifically bind to either huSCF or huCSF1.
5. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, which is a monoclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, or a chimeric antibody.
6. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment further comprises a heavy chain immunoglobulin constant domain selected from the group consisting of: (a) an IgA constant domain; (b) an IgD constant domain; (c) an IgE constant domain; (d) an IgG1 constant domain; (e) an IgG2 constant domain; (f) an IgG3 constant domain; (g) an IgG4 constant domain; and (h) an IgM constant domain; preferably, wherein the antibody or antigen-binding fragment comprises an IgG1 constant domain. 77
7. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment further comprises a light chain immunoglobulin constant domain selected from the group consisting of: (a) an Ig kappa constant domain; and (b) an Ig lambda constant domain.
8. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antigen binding protein comprises a human IgG1 heavy chain constant domain and a human lambda light chain constant domain; preferably wherein the IgG1 constant domain comprises one or more amino acid substitutions selected from the group consisting of L234F, L235E and P331S, numbered according to the EU numbering index of Kabat.
9. An isolated nucleic acid molecule encoding the antibody or antigen-binding fragment thereof according to any one of the preceding claims; preferably wherein the nucleic acid molecule is operably linked to a control sequence.
10. A vector comprising the nucleic acid molecule according to claim 9.
11. A host cell transformed with the nucleic acid of molecule of claim 9 or the vector of claim 10.
12. The host cell of claim 11, wherein the host cell is a mammalian host cell.
13. A hybridoma producing the antibody or antigen-binding fragment of any one of claims 1-8.
14. An isolated host cell producing the antibody or antigen-binding fragment of any one of claims 1-8.
15. A method of making the antibody or antigen-binding fragment thereof according to any one of claims 1-8, comprising (a) culturing a host cell expressing said antibody or antigen-binding fragment thereof; and (b) isolating said antibody or antigen-binding fragment thereof from said cultured host cell. 78
16. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1-8, and a pharmaceutically acceptable excipient; preferably wherein said pharmaceutical composition is for use as a medicament.
17. A method for treating nephritis, comprising: administering to a subject in need thereof a pharmaceutically effective amount of the antibody or antigen-binding fragment thereof according to any one of claims 1-8.
18. A method for treating primary Sjögren’s Syndrome, comprising: administering to a subject in need thereof a pharmaceutically effective amount of the antibody or antigen-binding fragment thereof according to any one of claims 1-8.
19. A method for treating myositis, comprising: administering to a subject in need thereof a pharmaceutically effective amount of the antibody or antigen-binding fragment thereof according to any one of claims 1-8.
20. A method for treating systemic lupus erythematosus (SLE), comprising: administering to a subject in need thereof a pharmaceutically effective amount of the antibody or antigen-binding fragment thereof according to any one of claims 1-8; preferably wherein the subject has increased serum levels FLT3L, as measured by frequency of FLT3Lexpressing CD4+ T cells, compared to a healthy subject.
21. A method for diagnosing systemic lupus erythematosus (SLE) in a subject, comprising: a. measuring serum levels of FLT3L; or b. measuring frequency of FLT3L-expressing CD4+ T cells, wherein increased serum levels of FLT3L or increased frequency of FLT3L-expressing CD4+ T cells in the subject compared to a healthy donor indicates that the subject has SLE; preferably wherein the CD4+ T cells are effector memory cells (TEM). 79
22. A method of neutralizing membrane bound FLT3L in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1-8.
23. The method of claim 22, wherein the FLT3L is reversibly neutralized.
24. A method of reducing populations of circulating classical dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1-8.
25. The method of claim 24, wherein the populations of cDCs and pDCs are reversibly reduced such that the populations of cDC and pDC are capable of returning to pre-administration levels.
26. A method of reducing FLT3L expression on CD4+ T cells, comprising administering to a subject in need thereof a pharmaceutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1-8.
27 A method of reducing the percentage of CD4+ T cells expressing FLT3L, comprising administering to a subject in need thereof a pharmaceutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1-8.
28. A method of reducing ERK signaling in a lymphoblast, comprising contacting the lymphoblast with an antibody or antigen-binding fragment thereof according to any one of claims 1-8.
29. A method of reducing MEK
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ807887A true NZ807887A (en) |
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