TARGETED IMMUNOTOLERANCE

1 . A polypeptide comprising:

i) a specific targeting moiety selected from:

a) a donor specific targeting moiety which, e.g., preferentially binds a donor target; or

b) a tissue specific targeting moiety which, e.g., preferentially binds target tissue of a subject; and

ii) an effector binding/modulating moiety selected from:

(a) an immune cell inhibitory molecule binding/modulating moiety (ICIM binding/modulating moiety);

(b) an immunosuppressive immune cell binding/modulating moiety (IIC binding/modulating moiety); or

(c) an effector binding/modulating moiety that, as part of a polypeptide, promotes an immuno-suppressive local microenvironment, e.g., by providing in the proximity of the target, a substance that inhibits or minimizes attack by the immune system of the target (SM binding/modulating moiety).

2 . The polypeptide of claim 1 , wherein the effector binding/modulating moiety directly binds and activates an inhibitory receptor.

3 - 10 . (canceled)

11 . The polypeptide of claim 1 , wherein the targeting moiety comprises an anti-MAdCAM antibody and the an effector binding/modulating moiety comprises an anti-PD-1 antibody.

12 - 16 . (canceled)

17 . The polypeptide of claim 1 , wherein the ICIM is wherein the inhibitory immune molecule counter ligand molecule engages a cognate inhibitory immune checkpoint molecule selected from PD-1, KIR2DL4, LILRB1, LILRB, or CTLA-4, and wherein the PD-1, KIR2DL4, LILRB1, LILRB, or CTLA-4 molecule is an antibody.

18 - 20 . (canceled)

21 . The polypeptide of claim 17 , wherein the antibody is an antibody that binds to PD-1 and is a PD-1 agonist.

22 - 23 . (canceled)

24 . The polypeptide of claim 1 , wherein the cell surface inhibitory molecule is an inhibitory immune checkpoint molecule selected from the group comprising PD-1, KIR2DL4, LILRB1, LILRB2, CTLA-4, or selected from Table 1.

25 . (canceled)

26 . The polypeptide of claim 1 , further comprising a second effector binding/modulating moiety that binds a different target than the effector binding/modulating moiety and comprises a IIC binding/modulating moiety, or an SM binding/modulating moiety.

27 - 34 . (canceled)

35 . The polypeptide of claim 1 , wherein the effector binding/modulating moiety comprises a cell surface molecule binder which binds or specifically binds, a cell surface molecule on an immunosuppressive immune cell, and wherein the immunosuppressive immune cell comprises a T regulatory cell, such as a Foxp3+CD25+ T regulatory cell.

36 . The polypeptide of claim 1 , wherein the effector binding/modulating moiety comprises an SM binding/modulating moiety selected from a CD39 molecule, or a CD73 molecule.

37 - 39 . (canceled)

40 . The therapeutic compound of claim 36 , wherein the SM binding/modulating moiety comprises an anti-CD39 antibody molecule, or an anti-CD73 antibody molecule.

41 . (canceled)

42 . 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,

each of Linker Region A and Linker Region B comprises an Fc region; and

R1, R2, R3, and R4, each independently comprises an effector binding/modulating moiety, e.g., an ICIM binding/modulating moiety, an IIC binding/modulating moiety, or an SM binding/modulating moiety; a specific targeting moiety; or

is absent;

provided that an effector binding/modulating moiety and a specific targeting moiety are present.

43 . (canceled)

44 . The polypeptide of claim 42 , wherein

one of R1 and R2 is anti-PD-1 antibody and one of R1 and R2 is an anti-MAdCAM antibody; or

one of R3 and R4 is anti-PD-1 antibody and one of R3 and R4 is an anti-MAdCAM antibody.

45 - 49 . (canceled)

50 . The polypeptide of claim 42 , wherein the linker is absent, is a Fc region, or is a glycine/serine linker.

51 - 52 . (canceled)

53 . The therapeutic compound of claim 44 , wherein the PD-1 antibody is a PD-1 agonist.

54 . The polypeptide of claim 44 , wherein:

R1 and R3 independently comprise a functional anti-PD-1 antibody molecule (an agonist of PD-1); and R2 and R4 independently comprise specific targeting moieties that bind to MAdCAM; or

R1 and R3 independently comprise specific targeting moieties that bind to MAdCAM; and R2 and R4 independently comprise a functional anti-PD-1 antibody molecule (an agonist of PD-1).

55 - 58 . (canceled)

59 . The polypeptide of claim 1 , wherein the targeting moiety comprises an antibody that binds or specifically binds to MAdCAM and the effector binding/modulating moiety comprises an antibody that binds to PD-1.

60 . A method of treating a subject with inflammatory bowel disease, Crohn's disease, ulcerative colitis, auto-immune hepatitis, sclerosing cholangitis, Type 1 diabetes, a transplant subject, GVHD, or a subject having, or at risk, or elevated risk, for having, an autoimmune disorder, the method comprising administering a polypeptide of claim 1 to the subject to treat the inflammatory bowel disease, Crohn's disease, ulcerative colitis, auto-immune hepatitis, sclerosing cholangitis, Type 1 diabetes, the transplant subject, GVHD, or the subject having, or at risk, or elevated risk, for having, an autoimmune disorder.

61 - 68 . (canceled)

69 . A nucleic acid molecule encoding a polypeptide of claim 1 .

70 . (canceled)

71 . A cell comprising the nucleic acid molecule of claim 59 .

72 - 74 . (canceled)

75 . A pharmaceutical composition comprising a polypeptide of claim 1 .