Method of inhibiting the proliferation of B cell cancers using TACI-immunoglobulin fusion proteins
Molecules that interfere with the binding of a tumor necrosis factor receptor with its ligand, such as a soluble receptor, have proven usefulness in both basic research and as therapeutics. The present invention provides improved soluble transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI) receptors.
1. A method for inhibiting the proliferation of B cell cancers comprising administering to the tumor cells in need thereof a composition comprising a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI)-immunoglobulin fusion protein, wherein the TACI-immunoglobulin fusion protein comprises:
(a) a TACI receptor moiety that consists off
i) amino acid residues 30-110 of SEQ ID NO:2; or,
ii) amino acid residues 30-154 of SEQ ID NO:2;
wherein the TACI receptor moiety binds at least one of ZTNF2 or ZTNF4, and
(b) an immunoglobulin moiety comprising a CH2 and CH3 domain.
2. The method of claim 1 , wherein the composition comprises a pharmaceutical composition that comprises the TACI-immunoglobulin fusion protein and a pharmaceutically acceptable carrier, and wherein the pharmaceutical composition is administered to a mammalian subject which has a B cell cancer.
3. The method of claim 2 , wherein the administration of the pharmaceutical composition inhibits the proliferation of B lymphocytes in the mammalian subject.
4. The method of claim 1 , wherein the immunoglobulin moiety is an IgG1 immunoglobulin moiety.
5. The method of claim 4 , wherein the immunoglobulin moiety is an IgG1 Fc fragment that comprises a disulfide linked heavy chain hinge region, a C H2 domain and a C H3 domain.
6. The method of claim 1 , wherein the TACI-immunoglobulin fusion protein has an amino acid sequence of SEQ ID NO:54.
7. The method of claim 1 , wherein the TACI-immunoglobulin fusion protein has an amino acid sequence comprising the secreted form of the amino acid sequence of SEQ ID NO:54.
8. The method of claim 1 , wherein the TACI-immunoglobulin fusion protein comprises the amino acid sequence of SEQ ID NO:54, wherein the optimized tPA (otPA) leader sequence (SEQ ID NO:25) has been removed.
9. The method of claim 1 , wherein the composition is administered to cells cultured in vitro.
10. The method of claim 1 , wherein the TACI-immunoglobulin fusion protein is a dimer.
11. A method for reducing circulating blood levels of ZTNF4 in a mammalian subject comprising administering to the mammalian subject a composition comprising a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI)-immunoglobulin fusion protein, wherein the TACI-immunoglobulin fusion protein comprises:
(a) a TACI receptor moiety that consists of
i) amino acid residues 30-110 of SEQ ID NO:2; or,
ii) amino acid residues 30-154 of SEQ ID NO:2;
wherein the TACI receptor moiety binds ZTNF4, and
(b) an immunoglobulin moiety comprising a C H2 and C H3 domain.
12. The method of claim 11 , wherein the immunoglobulin moiety is an IgG1 immunoglobulin moiety.
13. The method of claim 12 , wherein the immunoglobulin moiety is an IgG1 Fc fragment that comprises a disulfide linked heavy chain hinge region, a C H2 domain and a C H3 domain.
14. The method of claim 11 , wherein the TACI-immunoglobulin fusion protein has an amino acid sequence of SEQ ID NO:54.
15. The method of claim 11 , wherein the TACI-immunoglobulin fusion protein has an amino acid sequence comprising the secreted form of the amino acid sequence of SEQ ID NO:54.
16. The method of claim 11 , wherein the TACI-immunoglobulin fusion protein comprises the amino acid sequence of SEQ ID NO:54, wherein the optimized tPA (otPA) leader sequence (SEQ ID NO:25) has been removed.
17. The method of claim 11 , wherein the composition is administered to cells cultured in vitro.
18. The method of claim 11 , wherein the TACI-immunoglobulin fusion protein is a dimer.