TISSUE TARGETED IMMUNOTOLERANCE WITH PD-1 AGONISTS OR IL-2 MUTEINS

1 . A polypeptide comprising a skin targeting moiety or an intestine target moiety that binds to a target cell in the skin or the intestine and an effector binding/modulating moiety, wherein the effector binding/modulating moiety is a PD-1 agonist or an 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 the skin cell.

3 . The polypeptide of claim 2 , wherein the antibody is an antibody that binds to a desmoglein protein.

4 . The polypeptide of claim 1 , wherein the IL-2 mutein binds to a receptor expressed by an immune cell.

5 . The polypeptide of claim 4 , wherein the immune cell contributes to an unwanted immune response.

6 . The polypeptide of claim 4 , wherein the immune cell causes a disease pathology.

7 . The polypeptide of claim 1 , wherein the targeting moiety comprises an anti-desmoglein 1 antibody, an anti-desmoglein 2 antibody, an anti-desmoglein 3 antibody, or an anti-desmoglein 4 antibody.

8 .- 41 . (canceled)

42 . A polypeptide comprising a skin targeting moiety or an intestine target moiety that binds to a target cell in the skin or the intestine and an effector binding/modulating moiety, wherein the effector binding/modulating moiety is a PD-1 agonist or an 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 the amino acids at position 53, 56, 80 or 118 is I and the remainder are L or I, wherein the polypeptide comprises a first chain and a second chain, wherein

the first chain comprises:

V H -H c -Linker-C 1 , wherein V H is a variable heavy domain that binds to the target cell with a V L domain of the second chain; H c is a heavy chain of antibody comprising CH1-CH2-CH3 domain, the Linker is a glycine/serine linker, and C 1 is an 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 V H domain of the first chain, and the L c domain is a light chain CK domain.

43 . The polypeptide of claim 42 , wherein the V L and V H domain are anti-desmoglein 1, 2, 3, or 4 variable domains that bind to desmoglein 1, 2, 3, or 4 expressed on a cell.

44 . (canceled)

45 . (canceled)

46 . The polypeptide of claim 42 , wherein the IL-2 mutein further comprises a mutation at a position that corresponds to position 69, 75, 88, or 125, or any combination thereof.

47 . The polypeptide of claim 42 , wherein the IL-2 mutein comprises a mutation selected from the group consisting of: at one of L53I, L56I, L80I, and L118I and the mutations of V69A, Q74P, N88D or N88R, and optionally C125A or C125S.

48 . The polypeptide of claim 47 , wherein the IL-2 mutein comprises a L53I mutation.

49 . The polypeptide of claim 47 , wherein the IL-2 mutein comprises a L56I mutation.

50 . The polypeptide of claim 47 , wherein the IL-2 mutein comprises a L80I mutation.

51 . The polypeptide of claim 47 , wherein the IL-2 mutein comprises a L118I mutation.

52 . The polypeptide of claim 42 , wherein the IL-2 mutein does not comprises any other mutations.

53 . The polypeptide of claim 42 , wherein the Fc protein comprises L247A, L248A, and G250A mutations, or a L234A mutation, a L235A mutation, and/or a G237A mutation according to Kabat numbering.

54 . The polypeptide of claim 42 , wherein the Linker comprises a sequence of GGGGSGGGGSGGGGS (SEQ ID NO: 30) or GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22).

55 .- 58 . (canceled)

59 . A method of treating a subject with inflammatory bowel disease, GVHD, a skin auto-immune disorder as provided herein, the method comprising administering a polypeptide of claim 1 to the subject to treat the inflammatory bowel disease.

60 . The method of claim 59 , wherein the subject with inflammatory bowel disease has Crohn's disease.

61 . The method of claim 59 , wherein the subject with inflammatory bowel disease has ulcerative colitis.

62 .- 102 . (canceled)