Optimized FC variants

Abstract

A variant of a parent polypeptide including an Fc region, which variant exhibits increased binding to FcRn as compared to the parent polypeptide and includes at least one amino acid modification in the Fc region.

The invention claimed is: 
     
       1. A variant of a parent polypeptide comprising a Fc region, which variant exhibits increased binding to FcRn as compared to said parent polypeptide and comprises
 a combination of amino acid modifications selected from the group consisting of:   N315D/A330V/N361D/A378V/N434Y,   V264E/N315D/A378V/N390S/G420R/N434Y,   N315D/A378V/N434Y,   N315D/A330V/A378V/N434Y,   N315D/K334E/A378V/N434Y,   V264E/N315D/A378V,   P228R/N315D/A330V/N361D/A378V/N434Y,   P228R/P230S/N315D/A330V/N361D/A378V/N434Y,   P228L/N315D/A330V/N361D/A378V/N434Y,   P228L/P230S/N315D/A330V/N361D/A378V/N434Y,   P230S/N315D/A330V/N361D/A378V/N434Y, and   P230T/V264E/N315D/K370R/A378V   of the Fc region, wherein the numbering of the amino acids in the Fc region is that of the EU index as in Kabat.   
     
     
       2. The variant according to  claim 1 , wherein said variant is an antibody. 
     
     
       3. The variant according to  claim 2 , wherein said antibody is an IgG antibody. 
     
     
       4. A pharmaceutical composition comprising a variant as defined in  claim 1 . 
     
     
       5. A medicament comprising a variant according to  claim 1 . 
     
     
       6. An isolated nucleic acid encoding a variant as defined in  claim 1 . 
     
     
       7. A vector comprising the nucleic acid of  claim 6 . 
     
     
       8. An isolated host cell containing the vector of  claim 7 . 
     
     
       9. A method for producing a variant according to  claim 1 , comprising culturing a host cell containing a vector comprising an isolated nucleic acid encoding said variant so that the nucleic acid is expressed. 
     
     
       10. A variant of a parent polypeptide comprising a Fc region, which variant exhibits increased binding to FcRn as compared to said parent polypeptide and comprises from 2 to 7 amino acid modifications, said amino acid modifications comprising:
 (i) one amino acid modification selected from the group consisting of 434Y and 434S, and   (ii) at least one amino acid modification selected from the group consisting of 226G, P228L, P228R, 230S, 230T, 230L, 241L, 264E, 307P, 315D, 330V, 362R, 378V, 378T, 389T, 389K, 434Y and 434S   of the Fc region, wherein the numbering of the amino acids in the Fc region is that of the EU index as in Kabat and with the proviso that the modification (i) does not occur at the same amino acid position as the modification (ii).   
     
     
       11. The variant according to claim 10, said variant comprising at least one combination of amino acid modifications selected from the group consisting of:
 226G/315D/434Y, 230S/315D/434Y, 230T/315D/434Y, 230T/264E/434S, 230T/389T/434S, 241L/264E/434S, 250A/389K/434Y, 259I/315D/434Y, 264E/378V/434S, 264E/396L/434S, 294del/307P/434Y, 307P/378V/434Y, 315D/330V/434Y, 315D/382V/434Y and 378V/383N/434Y of the Fc region as compared to said parent polypeptide, wherein the numbering of the amino acids in the Fc region is that of the EU index as in Kabat.   
     
     
       12. The variant according to claim 11, wherein the said variant further comprises at least one amino acid modification selected from the group consisting of 226G, 227L, 230S, 230T, 230L, 231T, 241L, 243L, 250A, 256N, 259I, 264E, 265G, 267R, 290E, 294del, 303A, 305A, 307P, 307A, 308I, 315D, 322R, 325S, 327V, 330V, 342R, 347R, 352S, 361D, 362R, 362E, 370R, 378V, 378T, 382V, 383N, 386R, 386K, 387T, 389T, 389K, 392R, 395A, 396L, 397M, 403T, 404L, 415N, 416K, 421T, 426T, 428L, 433R, 434Y, 434S and 439R of the Fc region, as compared to the parent polypeptide, wherein the numbering of the amino acids in the Fc region is that of the EU index as in Kabat. 
     
     
       13. The variant according to claim 10, wherein the said variant comprises one combination of amino acid modifications selecting from the group consisting of 307A/315D/330V/382V/389T/434Y, 256N/378V/383N/434Y, 315D/330V/361D/378V/434Y, 259I/315D/434Y, 230S/315D/428L/434Y, 250A/389K/434Y, 305A/315D/330V/395A/434Y, 264E/386R/396L/434S/439R, 315D/330V/362R/434Y, 294del/307P/434Y, 305A/315D/330V/389K/434Y, 315D/327V/330V/397M/434Y, 264E/396L/415N/434S, 227L/264E/378V/434S, 230T/315D/362R/426T/434Y, 226G/315D/330V/434Y, 250A/315D/325S/330V/434Y, 290E/315D/342R/382V/434Y, 241L/315D/330V/392R/434Y, 241L/264E/307P/378V/434S, 230T/264E/403T/434S, 230T/315D/362E/434Y, 226G/315D/434Y, 226G/315D/362R/434Y, 226G/264E/347R/370R/378V/434S, 308I/315D/330V/382V/434Y, 230T/264E/378V/434S, 231T/241L/264E/378T/397M/434S, 230L/264E/378V/434S, 230T/315D/330V/386K/434Y, 226G/315D/330V/389T/434Y, 267R/307P/378V/421T/434Y, 230S/315D/387T/434Y, 230S/264E/352S/378V/434S and 230T/303A/322R/389T/404L/434S of the Fc region as compared to said parent polypeptide, wherein the numbering of the amino acids in the Fc region is that of the EU index as in Kabat. 
     
     
       14. The variant according to claim 13, wherein the said variant comprises a combination of amino acid modifications selecting from the group consisting of:
 T307A/N315D/A330V/E382V/N389T/N434Y,   T256N/A378V/S383N/N434Y,   N315D/A330V/N361D/A378V/N434Y,   V259I/N315D/N434Y,   P230S/N315D/M428L/N434Y, and   E294del/T307P/N434Y,   of the Fc region, wherein the numbering of the amino acids in the Fc region is that of the EU index as in Kabat.   
     
     
       15. The variant according to claim 14, wherein said variant is an antibody. 
     
     
       16. The variant according to claim 15, wherein said antibody is an IgG antibody. 
     
     
       17. A pharmaceutical composition comprising a variant as defined in claim 13. 
     
     
       18. An isolated nucleic acid encoding a variant as defined in claim 13. 
     
     
       19. A vector comprising the nucleic acid of claim 18. 
     
     
       20. An isolated host cell containing the vector of claim 19. 
     
     
       21. A method for producing a variant according to claim 13, comprising culturing a host cell containing a vector comprising an isolated nucleic acid encoding said variant so that the nucleic acid is expressed. 
     
     
       22. A variant according to claim 10, wherein the Fc region of the of a parent polypeptide is SEQ ID NO: 1 or SEQ ID NO: 2.