BTLA fusion protein agonists and uses thereof
The present invention is based on the seminal discovery that BTLA agonist fusion proteins modulate an immune response. Specifically, the present invention provides fusion proteins that bind BTLA enhancing BTLA signaling. The present invention further provides methods of treating cancer and immune and inflammatory diseases and disorders with a BTLA agonist fusion protein as described herein.
1. A fusion protein comprising an herpesvirus entry mediator (HVEM) protein and an Fc protein, wherein the HVEM protein comprises an extracellular domain and wherein the HVEM protein comprises at least one amino acid mutation selected from the group consisting of an amino acid mutation at residues 58, 68, 70, and 90 of SEQ ID NO:2, wherein the at least one amino acid mutation is selected from S58R, S58K, S58Q, G68T, L70D, L70E, L70N, L70W, and L90A of SEQ ID NO: 2.
2. A fusion protein comprising an herpesvirus entry mediator (HVEM) protein and an Fc protein, wherein the HVEM protein comprises an extracellular domain and wherein the HVEM protein comprises at least one amino acid mutation selected from the group consisting of an amino acid mutation at residues 58, 68, 70, and 90 of SEQ ID NO:2, wherein the at least one amino acid mutation is selected from the group consisting of:
a) S58R;
b) S58K;
c) S58Q;
d) L70D;
e) L70E;
f) L70N;
g) L90A;
h) S58R and L90A;
i) S58R and G68T;
j) S58R and L70W;
k) S58R, L70D and L90A;
l) S58R, G68T and L90A;
m) S58R, L70W and L90A;
n) S58R, G68T, L70D and L90A; and
o) S58R, G68T, L70W and L90A of SEQ ID NO: 2.
3. The fusion protein of claim 2 , wherein the at least one amino acid mutation comprises S58R, G68T, L70W and L90A of SEQ ID NO: 2.
4. A pharmaceutical composition comprising: (a) a fusion protein comprising a non-naturally occurring herpesvirus entry mediator (HVEM) protein and an Fc protein; and (b) a pharmaceutically acceptable carrier, wherein the HVEM protein comprises an extracellular domain and at least one amino acid mutation selected from the group consisting of an amino acid mutation at residues 58, 68, 70, and 90 of SEQ ID NO: 2, wherein the at least one mutation in the HVEM protein is selected from the group consisting of:
a) S58R;
b) S58K;
c) S58Q;
d) L70D;
e) L70E;
f) L70N;
g) L90A;
h) S58R and L90A;
i) S58R and G68T;
j) S58R and L70W;
k) S58R, L70D and L90A;
l) S58R, G68T and L90A;
m) S58R, L70W and L90A;
n) S58R, G68T, L70D and L90A; and
o) S58R, G68T, L70W and L90A of SEQ ID NO: 2.
5. A herpesvirus entry mediator (HVEM) protein comprising mutations S58R, G68T, L70W and L90A of SEQ ID NO: 2.