BAFF variants and methods thereof
The invention relates to novel proteins with BAFF dominant negative antagonist, receptor antagonist activity and agonist activity and nucleic acids encoding these proteins. The invention further relates to the use of the novel proteins in the treatment of BAFF or APRIL-related disorders.
1. An isolated B cell Activation Factor (BAFF) protein wherein the BAFF variant differs from residues 144-284 of wild type human BAFF corresponding to residues 1-141 set forth in SEQ ID NO: 8 by two or three amino acid substitutions, wherein one of the substitutions is F220S, and wherein the BAFF variant has reduced BAFF receptor binding relative to wild-type human BAFF comprising SEQ ID NO: 8 and the BAFF receptor is selected form the group consisting of BAFFR, TACI and BCMA.
2. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is selected from the group consisting of: Q159D, Q159E, Q159K, Q159R, S162D, S162L, S162N, Y163A, Y163D, Y163E, Y163F, Y163H, Y163I, Y163K, Y163L, Y163R, Y163T, D203E, D203G, D203K, D203N, D203S, K204E, K204Q, T205A, T205D, T205I, T205K, T205L, T205N, T205S, Y206A, Y206E, Y206F, Y206I, Y206K, Y206Q, Y206S, A207S, A207T, L211D, L211E, L211K, L211V, T228N, T228V, R231 K, I233A, I233E, I233L, I233Q, I233T, I233V, I233Y, E238K, E238Q, L240A, L240F, L240K, L240N, L240R, L240Y, N242A, N242S, N242Y, P264A, P264D, P264N, R265A, R265H, R265K, R265L, E266A, E266D, E266I, E266K, E266L, E266Q, E266R, E266T, N267R, N267S, Q269E, Q269H, Q269K, S271E, S271R, D273A, D273E, D273H, D273N, D273R, D275A, D275E, D275H, D275K, D275N, D275R, and D275V.
3. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is selected from the group consisting of: Q159E, Q159D, Y163E, Y163K, Y163R, D203S, D203N, D203E, K204E, K204Q, T205A, T205K, T205N, T205S, T205D, T205L, Y206A, Y206E, Y206K, Y206Q, Y206S, Y206I, A207S, L211K, L211D, T228N, T228V, R231K, I233A, I233E, I233T, I233Q, I233Y, 264N, 264D, 264A, R265A, R265K, R265L, R265H, E266Q, E266D, N267S, S271R, D275A, D275V, D275K, D275R, D275H, and D275N.
4. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is selected from the group consisting of: T205D, Y206K, I233E, I233Y, R265K, D275A, and D275R.
5. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is T205D.
6. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is Y206K.
7. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is I233E.
8. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is I233Y.
9. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is R265K.
10. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is D275A.
11. The variant BAFF protein according to claim 1 , wherein the second or third amino acid substitution is D275R.