TARGETED IMMUNOTOLERANCE
Methods and compounds for conferring site-specific or local immune privilege.
1 . A polypeptide comprising a targeting moiety that binds to a target cell and an effector binding/modulating moiety, wherein the effector binding/modulating moiety is a IL-2 mutein polypeptide (IL-2 mutein), wherein the IL-2 mutein comprises the sequence of SEQ ID NO: 60, wherein at least one of X 1 , X 2 , X 3 , and X 4 is I and the remainder are L or I.
2 . The polypeptide of claim 1 , wherein the targeting moiety comprises an antibody that binds to a target protein on the surface of a target cell.
3 . The polypeptide of claim 1 , wherein the antibody is an antibody that binds to MAdCAM, OAT1, OCT2, FXYD2, TSPAN7, DPP6, HEPACAM2, TMEM27, or GPR119.
4 - 7 . (canceled)
8 . The polypeptide of claim 1 , wherein the compound has the formula from N-terminus to C-terminus:
R1-Linker Region A-R2 or R3-Linker Region B-R4,
wherein,
R1, R2, R3, and R4, each independently comprises the effector binding/modulating moiety, the targeting moiety, or is absent.
9 . The polypeptide of claim 8 , wherein each of Linker Region A and Linker Region B comprises an Fc region.
10 . The polypeptide of claim 9 , wherein one of R1 and R2 is the IL-mutein antibody and one of R1 and R2 is an anti-MAdCAM antibody.
11 . The polypeptide of claim 8 , wherein R1 is the IL-mutein and R2 is an anti-MAdCAM antibody.
12 . The polypeptide of claim 8 , wherein one of R1 is anti-MAdCAM antibody and one R2 is an anti-PD-1 antibody.
13 . The polypeptide of claim 8 , wherein one of R3 and R4 is the IL-2 mutein and one of R3 and R4 is an anti-MAdCAM antibody.
14 . The polypeptide of claim 8 , wherein R3 is the IL-2 mutein and R4 is an anti-MAdCAM antibody.
15 . The polypeptide of claim 8 , wherein R3 is an anti-MAdCAM antibody and one R4 is the IL-2 mutein.
16 . The polypeptide of claim 8 , wherein the linker is absent.
17 . The polypeptide of claim 8 , wherein the linker is a Fc region.
18 . The polypeptide of claim 8 , wherein the linker is a glycine/serine linker.
19 . (canceled)
20 . The polypeptide of claim 1 , wherein the IL-2 mutein comprises a IL-2 sequence of SEQ ID NO: 6, wherein peptide comprises a mutation at a position that corresponds to position 53, 56, 80, or 118 of SEQ ID NO: 6.
21 - 41 . (canceled)
42 . The polypeptide of claim 1 , wherein the polypeptide comprises a first chain and a second chain that form the polypeptide, wherein
the first chain comprises:
V H -H c -Linker-C 1 , wherein VH is a variable heavy domain that binds to the target cell with a V L domain of the second chain; He is a heavy chain of antibody comprising CH1-CH2-CH3 domain, the Linker is a glycine/serine linker, and C 1 is a IL-2 mutein fused to a Fc protein in either the N-terminal or C-terminal orientation; and
the second chain comprises:
V L -L c , wherein V L is a variable light chain domain that binds to the target cell with the VH domain of the first chain, and the L c domain is a light chain CK domain.
43 - 55 . (canceled)
56 . A method of treating a subject with inflammatory bowel disease, the method comprising administering a polypeptide of claim 1 to the subject to treat the inflammatory bowel disease.
57 - 58 . (canceled)
59 . A method of treating a subject with auto-immune hepatitis, the method comprising administering a therapeutic compound of claim 1 to the subject to treat the auto-immune hepatitis.
60 - 63 . (canceled)
64 . A method of treating a subject having, or at risk, or elevated risk, for having, an autoimmune disorder, comprising administering a therapeutically effective amount of a therapeutic compound of claim 1 , thereby treating the subject.
65 - 70 . (canceled)
71 . A cell comprising a nucleic acid molecule encoding a therapeutic compound of claim 1 .