Tissue targeted immunotolerance with a CD39 effector
Methods and compounds for conferring site-specific or local immune privilege, such as to the skin.
1. A polypeptide comprising a skin targeting moiety that binds to a target cell and an effector binding/modulating moiety, wherein the skin targeting moiety comprises an anti-desmoglein 1 antibody comprising a variable heavy domain having the amino acid sequence of SEQ ID NO: 65 and a variable light domain having the amino acid sequence of SEQ ID NO: 66, wherein the effector binding/modulating moiety is a CD39 Effector Domain, 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 polypeptide has the formula from N-terminus to C-terminus:
R1---Linker Region A-R2 or R3-Linker Region B-R4,
wherein,
R1 and R4, each independently comprise an effector binding/modulating moiety, wherein the effector binding/modulating moiety is a CD39 Effector Domain, 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; and
R2 and R3, each independently comprise a skin targeting moiety that binds to a target cell, wherein the skin targeting moiety comprises an anti-desmoglein 1 antibody comprising a variable heavy domain having the amino acid sequence of SEQ ID NO: 65 and a variable light domain having the amino acid sequence of SEQ ID NO: 66.
3. The polypeptide of claim 2 , wherein:
(i) R1 is a CD39 Effector Domain, 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 and R2 a skin targeting moiety that binds to a target cell, wherein the skin targeting moiety comprises an anti-desmoglein 1 antibody comprising a variable heavy domain having the amino acid sequence of SEQ ID NO: 65 and a variable light domain having the amino acid sequence of SEQ ID NO: 66; and
(ii) R3 is a CD39 Effector Domain, 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 and R4 a skin targeting moiety that binds to a target cell, wherein the skin targeting moiety comprises an anti-desmoglein 1 antibody comprising a variable heavy domain having the amino acid sequence of SEQ ID NO: 65 and a variable light domain having the amino acid sequence of SEQ ID NO: 66.
4. The polypeptide of claim 1 , wherein the CD39 Effector Domain comprises a sequence of SEQ ID NO: 64 or SEQ ID NO: 61.
5. A nucleic acid molecule encoding a polypeptide of claim 1 .
6. A cell comprising the nucleic acid molecule of claim 5 .
7. A pharmaceutical composition comprising a polypeptide-of claim 1 and a pharmaceutically acceptable carrier.