Bcma Polypeptides and Uses Thereof

Abstract

The present invention relates to polypeptides that inhibit APRIL and/or BAFF binding to BCMA, nucleic acid molecules encoding the polypeptides, and compositions comprising the polypeptides. The present invention also relates to methods for treating an immune-related disease or cancer using the polypeptides and compositions of the invention. The present invention also relates to methods for identifying inhibitors of APRIL/BAFF binding to BCMA and APRIL/BAFF signaling.

1 . A polypeptide that binds APRIL comprising the sequence of Formula I:  
         C-X 2 -X 3 -X 4 -X 5 -Y-X 7 -D-X 9 -L X 11 -X 12 -X 13 -C-K-X 16 -C-X 18 -X 19 -X 20 -C-X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -C-X 31 -X 32 -X 33 -C  (Formula I)  wherein X 11  is any amino acid residue except A;    wherein X 2 , X 3 , X 4 , X 5 , X 7 , X 9 , X 11 , X 12 , X 13 , X 16 , X 18 , X 19 , X 20 , X 22 , X 23 , X 24 , X 25 , X 26 , X 27 , X 28 , X 29 , X 31 , X 32 , X 33  are any amino acid except cysteine.    
     
     
         2 . The polypeptide according to  claim 1 , wherein X 11  is L, I or V.  
     
     
         3 . The polypeptide according to  claim 1 , wherein X 18  is selected from the group consisting of Q, D and A.  
     
     
         4 . The polypeptide according to  claim 1 , wherein if X 20  is Y, then X 18  is D.  
     
     
         5 . The polypeptide according to  claim 1 , wherein X20 is R.  
     
     
         6 . The polypeptide according to  claim 1 , wherein the polypeptide comprises an amino acid sequence that is 85% or more identical to a CRD sequence of a native BCMA.  
     
     
         7 . The polypeptide according to  claim 1 , wherein the sequence of Formula I is selected from the group consisting of CSQNEYFDSLLHACKPCQLRCSSNTPPLTCQRYC, CSQNEYFDSLLHACKPCDLRCSSNTPPLTCQRYC, CSQNEYFDSLLHACKPCDLYCSSNTPPLTCQRYC, and CSQNEYFDSLVHACKPCQLRCSSNTPPLTCQRYC.  
     
     
         8 . A polypeptide that binds BAFF comprising the sequence of Formula II:  
         C-X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -D-X 9 -L-X 11 -X 12 -X 13 -C-X 15 -X 16 -C-X 18 -X 19 -X 20 -C-X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -C-X 31 -X 32 -X 33 -C  (Formula II)  wherein X 6  is selected from the group consisting of Y, A, D, S and F;    wherein X 11  is any amino acid residue except A;    wherein X 15  is any amino acid residue except A or K;    wherein X 18  is selected from the group consisting of Q, D and A;    wherein X 20  is selected from the group consisting of R, Y and A;    wherein X 2 , X 3 , X 4 , X 5 , X 7 , X 9 , X 10 , X 12 , X 13 , X 16 , X 19 , X 22 , X 23 , X 24 , X 25 , X 26 , X 27 , X 28 , X 29 , X 31 , X 32  and X 33  are any amino acid except cysteine; and    provided that the Formula II does not comprise the sequence CSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYC.    
     
     
         9 . The polypeptide according to  claim 8 , wherein X 11  is L, I or V.  
     
     
         10 . The polypeptide according to  claim 8 , wherein X 15  is I, V or A.  
     
     
         11 . The polypeptide according to  claim 8 , wherein X 18  is D and X 20  is Y.  
     
     
         12 . The polypeptide according to  claim 1 , wherein the polypeptide comprises an amino acid sequence that is 85% or more identical to a CRD sequence of a native BCMA.  
     
     
         13 . The polypeptide according to  claim 8 , wherein the sequence of Formula II is selected from the group consisting of CSQNEAFDSLLHACIPCQLRCSSNTPPLTCQRYC, CSQNESFDSLLHACIPCQLRCSSNTPPLTCQRYC, CSQNEFFDSLLHACIPCQLRCSSNTPPLTCQRYC, CSQNEYFDSLLHACIPCDLRCSSNTPPLTCQRYC, CSQNEYFDSLLHACIPCQLYCSSNTPPLTCQRYC, and CSQNEYFDSLLHACEPCDLYCSSNTPPLTCQRYC.  
     
     
         14 . The polypeptide according to  claim 1 , wherein the Formula I further comprises the sequence NSVKGT linked carboxy-terminal to the thirty-fourth residue.  
     
     
         15 . The polypeptide according to  claim 8 , wherein the Formula II further comprises the sequence NSVKGT linked carboxy-terminal to the thirty-fourth residue.  
     
     
         16 . The polypeptides according to  claim 1 , wherein the polypeptide comprises sequences N-terminal, C-terminal or both N-terminal and C-terminal to the sequence of Formula I or Formula II that are heterologous to a native BCMA polypeptide.  
     
     
         17 . A polypeptide that is a BCMA variant having an amino acid sequence derived from a mammalian BCMA polypeptide wherein at least one amino acid residue corresponding to the amino acid residue selected from the group Q10, E12, Y13, F14, 122, Q25 and R27 of  FIG. 5  is altered.  
     
     
         18 . The polypeptide according to  claim 17 , wherein the 122 has been substituted with K.  
     
     
         19 . The polypeptide according to  claim 17 , wherein the mammalian BCMA polypeptide is altered at a amino acid residue corresponding to 122 and an amino acid residue corresponding to any one of the residues F14 and Q25 of  FIG. 5 .  
     
     
         20 . The polypeptide according to  claim 17 , wherein the mammalian BCMA polypeptide is altered at a residue corresponding to R27 and a residue corresponding to any one of the residues Y13 and Q25 of  FIG. 5 .  
     
     
         21 . The polypeptide according to  claim 17 , wherein Q25 has been substituted with D and R27 has been substituted with Y.  
     
     
         22 . The polypeptide according to  claim 8 , wherein the polypeptide comprises an amino acid sequence that is 85% or more identical to a CRD sequence of a native BCMA.  
     
     
         23 . The polypeptide according to  claim 1 , wherein the polypeptide further comprises a leucine zipper.  
     
     
         24 . The polypeptide according to any  claim 1 , wherein the polypeptide is attached to a non-proteinaceous polymer.  
     
     
         25 . The polypeptide according to  claim 1 , wherein the polypeptide is an immunoadhesin.  
     
     
         26 . The polypeptide according to  claim 1 , wherein the polypeptide is an antibody.  
     
     
         27 . The polypeptide according to  claim 26  wherein the antibody is selected from the group consisting of a F(ab) antibody, F(ab′) 2  antibody and a scFv antibody.  
     
     
         28 . The polypeptide according to  claim 1 , wherein the polypeptide is attached to an agent selected from the group consisting of a growth inhibitory agent, a cytotoxic agent, a detection agent, an agent that improves the bioavailability of the polypeptide and an agent that improves the half-life of the polypeptide.  
     
     
         29 . The polypeptide according to  claim 28 , wherein said cytotoxic agent is selected from the group consisting of a toxin, an antibiotic and a radioactive isotope.  
     
     
         30 . A nucleic acid molecule encoding the polypeptide according to  claim 1 .  
     
     
         31 . A vector comprising the nucleic acid molecule according to  claim 30 .  
     
     
         32 . A host cell comprising the nucleic acid molecule according to  claim 30  or a vector comprising the nucleic acid molecule.  
     
     
         33 . A composition comprising the polypeptide according to  claim 1 , optionally further comprising a pharmaceutically acceptable carrier.  
     
     
         34 . A composition comprising the polypeptide according to  claim 1 , optionally further comprising a second therapeutic agent selected from the group consisting of an agent for treating an immune-related disease, a chemotherapeutic agent and a cytotoxic agent.  
     
     
         35 . A method for producing a polypeptide comprising the step of culturing a host cell comprising the vector according to  claim 31  under conditions suitable for expressing the polypeptide from the vector.  
     
     
         36 . A method for identifying an inhibitor of APRIL binding to BCMA comprising the step of detecting an inhibitor that partially or fully blocks the binding of the polypeptide according to  claim 1  and APRIL.  
     
     
         37 . A method for identifying an inhibitor of BAFF binding to BCMA comprising the step of detecting an inhibitor that partially or fully blocks the binding of the polypeptide according  claim 8  and BAFF.  
     
     
         38 . A method for inhibiting native APRIL binding to native BCMA comprising the step of contacting an APRIL polypeptide with the polypeptide according to  claim 1 .  
     
     
         39 . A method for inhibiting native BAFF binding to native BCMA comprising the step of contacting a BAFF polypeptide with the polypeptide according to  claim 8 .  
     
     
         40 . A method for inhibiting native APRIL and/or native BAFF binding to native BCMA comprising the step of contacting an APRIL polypeptide or a BAFF polypeptide with the polypeptide according to  claim 17 .  
     
     
         41 . A method for inhibiting native APRIL binding to native BCMA in a mammal comprising the step of administering the polypeptide according to  claim 1  in an amount effective to inhibit binding between APRIL and BCMA in the mammal.  
     
     
         42 . A method for inhibiting native BAFF binding to native BCMA in a mammal comprising the step of administering the polypeptide according to  claim 8  in an amount effective to inhibit binding between BAFF and BCMA in the mammal.  
     
     
         43 . A method for inhibiting native BAFF and/or native APRIL binding to native BCMA in a mammal comprising the step of administering the polypeptide according to  claim 17  to the mammal.  
     
     
         44 . A method for treating an immune-related disease in a mammal suffering from an immune disease comprising the step of treating the mammal with a therapeutically effective amount of the polypeptide according to  claim 1 .  
     
     
         45 . The method according to  claim 44 , wherein the immune related disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosis.  
     
     
         46 . A method for treating a cancer in a mammal suffering from a cancer comprising the step of treating the mammal with a therapeutically effective amount of the polypeptide according to  claim 1 .  
     
     
         47 . The method according to  claim 46 , wherein said cancer is selected from the group consisting of leukemia, lymphoma, or multiple myeloma.  
     
     
         48 . The method according to  claim 46 , wherein said cancer is a gastrointestinal cancer or a glioblastoma.  
     
     
         49 . A method for treating a T-cell mediated disease in a mammal suffering from a T-cell mediated disease comprising the step of treating the mammal with a therapeutically effective amount of the polypeptide according to  claim 1 .  
     
     
         50 . The method according to  claim 49 , wherein the T-cell mediated disease is selected from the group consisting of graft rejection, graft verses host disease (GVHD) and inflammation.