Anti-inflammatory molecules with tissue-targeting functions
The present disclosure provides various molecular constructs having a targeting element and an effector element. Methods for treating various diseases using such molecular constructs are also disclosed.
1 . A molecular construct comprising,
a pair of CH2-CH3 segments of an IgG.Fc;
a first pair of effector elements, wherein the effector element is an antibody fragment specific for tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), IL-17 receptor (IL-17R), IL-1, IL-6, IL-6R, IL-12, IL-23, B cell activating factor (BAFF), or receptor activator of nuclear factor kappa-B ligand (RANKL); or a soluble receptor of TNF-α or IL-1; and
a first pair of targeting elements, wherein the targeting element is an antibody fragment specific for α-aggrecan, collagen I, collagen II, collagen III, collagen V, collagen VII, collagen IX, collagen XI, or osteonectin, wherein,
when the first pair of effector elements is linked to the N-termini of the pair of CH2-CH3 segments, then the first pair of targeting elements is linked to the C-termini of the pair of CH2-CH3 segments, and vice versa, or
when the first pair of effectors elements and the first pair of targeting elements are both in the form of single-chain variable fragments (scFvs), then the first pair of targeting elements is linked to the N-termini of the first pair of effector elements in a tandem or diabody configuration, thereby forming a pair of bispecific scFvs that are linked to the N-termini of the pair of CH2-CH3 segments.
2 . The molecular construct of claim 1 , wherein the pair of CH2-CH3 segments is derived from human γ4 or γ1 immunoglobulin.
3 . The molecular construct of claim 1 , wherein when the first pair of effector elements is in the form of an antigen-binding fragment (Fab), and the first pair of targeting elements is in the form of scFvs, and vice versa; then the Fab and scFvs are respectively linked to the N-termini and C-termini of the CH2-CH3 segments, so that molecular construct adopts an extended IgG configuration.
4 . The molecular construct of claim 1 , further comprising a second pair of effector elements or a second pair of targeting elements, wherein the second pair of effector or targeting elements is linked to the free C-termini of the CH2-CH3 segments.
5 . The molecular construct of claim 1 , wherein,
the effector element is an scFv specific for TNF-α; and
the targeting element is an scFv specific for collagen II, collagen IX, or α-aggrecan.
6 . The molecular construct of claim 1 , wherein,
the two effector elements are in the form of a Fab antibody specific for TNF-α; and
the targeting element is an scFv specific for collagen II or collagen IX.
7 . The molecular construct of claim 1 , wherein,
the effector element is an scFv specific for IL-17; and
the targeting element is an scFv specific for collagen I or collagen VII.
8 . The molecular construct of claim 1 , wherein,
the two effector elements are in the form of a Fab antibody specific for IL-17; and
the targeting element is an scFv specific for collagen I or collagen VII.
9 . The molecular construct of claim 1 , wherein,
the effector element is an scFv specific for BAFF; and
the targeting element is an scFv specific for collagen I or collagen VII.
10 . The molecular construct of claim 1 , wherein,
the two effector elements are in the form of a Fab antibody specific for BAFF; and
the targeting element is an scFv specific for collagen I or collagen VII.
11 . The molecular construct of claim 1 , wherein,
the effector element is an scFv specific for TNF-α; and
the targeting element is an scFv specific for collagen III or collagen V.
12 . The molecular construct of claim 1 , wherein,
the two effector elements are in the form of a Fab antibody specific for TNF-α; and
the targeting element is an scFv specific for collagen III or collagen V.
13 . The molecular construct of claim 1 , wherein,
the effector element is an scFv specific for RANKL; and
the targeting element is an scFv specific for collagen I or osteonectin.
14 . The molecular construct of claim 1 , wherein,
the two effector elements are in the form of a Fab specific for RANKL; and
the targeting element is an scFv specific for collagen I or osteonectin.
15 . A method for treating an immune disorder, comprising the step of administering to a subject in need thereof an effective amount of the molecular construct according to claim 1 .
16 . The method of claim 15 , wherein the immune disorder is an autoimmune disease.
17 . The method of claim 16 , wherein,
the autoimmune disease is rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis;
the effector element is an antibody fragment specific for TNF-α, IL-12/IL-23, IL-1, IL-17, or IL-6; and
the targeting element is an antibody fragment specific for collagen II, collagen IX, collagen XI, or α-aggrecan.
18 . The method of claim 16 , wherein,
the autoimmune disease is psoriasis;
the effector element is an antibody fragment specific for TNF-α, IL-12/IL-23, or IL-17; and
the targeting element is an antibody fragment specific for collagen I or collagen VII.
19 . The method of claim 16 , wherein,
the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, or Sjögren's Syndrome;
the effector element is an antibody fragment specific for BAFF; and
the targeting element is an antibody fragment specific for collagen I or collagen VII.
20 . The method of claim 16 , wherein,
the autoimmune disease is an inflammatory bowel disease;
the effector element is an antibody fragment specific for TNF-α; and
the targeting element is an antibody fragment specific for collagen III or collagen V.
21 . The method of claim 20 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
22 . A method for treating osteoporosis, comprising the step of administering to a subject in need thereof an effective amount of the molecular construct according to claim 1 .
23 . The method of claim 22 , wherein,
of the effector element is an antibody fragment specific for RANKL; and
the targeting element is an antibody fragment specific for collagen I or osteonectin.