CTLA4-Ig immunoadhesins
The present application relates to CTLA4-Ig immunoadhesins that target CD80 and CD86, and their use, particularly for therapeutic purposes.
1. A method of inhibiting T cell activation in the presence of B7-expressing antigen presenting cells (APCs) comprising contacting said T cells with an immunoadhesin, said immunoadhesin comprising a first domain comprising a variant CTLA4 as compared to SEQ ID NO:6 and a second domain comprising an IgG Fc region, wherein said variant CTLA4 comprises an amino acid modification selected from the group consisting of T51N, A29H, M53Y, L61E, and K93Q, wherein the binding of said variant CTLA4 to B7-1 (CD80) and/or B7-2 (CD86) is increased as compared to SEQ ID NO:6.
2. The method of claim 1 , wherein said B7-expressing antigen presenting cells express B7-2.
3. The method of claim 1 , wherein the modification is T51N.
4. The method of claim 1 , wherein the modification is A29H.
5. The method of claim 1 , wherein the modification is M53Y.
6. The method of claim 1 , wherein the modification is L61E.
7. The method of claim 1 , wherein the modification is K93Q.
8. The method of claim 1 , wherein the CTLA4 variant comprises a combination of substitutions selected from the group consisting of T51N/L61E/K93Q, A29H/T51N/L61E/K93Q, A29H/T51N, T51N/M53Y, and T51N/M53Y/L61E.
9. The method of claim 1 , wherein the IgG is IgG1.
10. The method of claim 1 , wherein the IgG is IgG2.
11. The method of claim 1 , wherein the IgG is an IgG1/IgG2 hybrid.
12. The method of claim 1 , wherein the B7-1 and/or B7-2 is expressed on peripheral blood monocyte cells (PBMCs).
13. The method of claim 8 , wherein the CTLA4 variant comprises T51N/L61E/K93Q.
14. The method of claim 8 , wherein the CTLA4 variant comprises A29H/T51N/L61E/K93Q.
15. The method of claim 8 , wherein the CTLA4 variant comprises A29H/T51N.
16. The method of claim 8 , wherein the CTLA4 variant comprises T51N/M53Y.
17. The method of claim 8 , wherein the CTLA4 variant comprises T51N/M53Y/L61E.
18. The method of claim 8 , wherein the CTLA4 variant further comprises a variant Fc region.
19. The method of claim 18 , wherein the variant Fc region comprises an amino acid modification selected from the group consisting of 259I, 308F, 428L, and 434S.
20. The method of claim 19 , wherein the modification is 434S.
21. The method of claim 19 , wherein the modification is 428L/434S.
22. The method of claim 19 , wherein the modification is 308F/259I.
23. The method of claim 19 , wherein the modification is 259I/308F/428L.