US2004132101A1PendingUtilityA1
Optimized Fc variants and methods for their generation

Assignee: XENCOR INCPriority: Sep 27, 2002Filed: Sep 26, 2003Published: Jul 8, 2004
Est. expirySep 27, 2022(expired)· nominal 20-yr term from priority
Inventors:Gregory Alan Lazar Arthur J. Chirino Wei Dang John Desjarlais Stephen K. Doberstein Robert Hayes Sher Bahadur Karki Omid Vafa
A61P 37/04A61P 37/02A61P 35/00C07K 2317/734C07K 2317/33G16C 20/60G16B 35/00C07K 2317/76C07K 16/2863G16B 15/00C07K 2317/732C07K 2317/21C07K 16/00C07K 16/22C07K 2317/52C07K 16/2896C07K 2317/34A61K 2039/505C07K 2317/24C07K 2317/72A61K 39/39566A61K 39/3955A61P 25/00C07K 16/2875C07K 2317/14G16B 5/00C07K 2317/71C07K 2317/56C07K 16/2893C07K 2317/77C07K 16/32A61K 39/395C12P 21/005G16B 30/00C07K 2317/41C07K 2317/524C07K 2317/526C07K 2317/92C07K 16/2887C07K 2317/51C07K 16/4291C07K 2319/30C07K 16/283A61P 29/00C07K 2317/522C07K 16/24G16B 15/20G16B 30/10A61P 9/00
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References
Claims
Abstract

The present invention relates to optimized Fc variants, methods for their generation, and antibodies and Fc fusions comprising optimized Fc variants.
Claims

exact text as granted — not AI-modified
We claim:  
     
         1 . An antibody comprising an Fc variant portion comprising at least one amino acid modification in the Fc region of said parent Fc polypeptide, wherein said Fc variant modulates binding to an FcγR as compared to the parent Fc polypeptide.  
     
     
         2 . An antibody according to  claim 1  wherein said modulation is an increase in affinity of said antibody to said FcγR.  
     
     
         3 . An antibody according to  claim 1  wherein said Fc variant portion comprises at least one substitution at a position corresponding to a position of the human sequence selected from the group consisting of: 234, 235, 239, 240, 241, 243, 244, 245, 247, 262, 263, 264, 265, 266, 267, 269, 296, 297, 298, 299, 313, 325, 326, 327, 328, 329, 330, 332, 333, and 334.  
     
     
         4 . An antibody according to  claim 1 , wherein said Fc variant comprises at least one substitution at a position corresponding to a position of the human sequence selected from the group consisting of: 240, 244, 245, 247, 262, 263, 266, 299, 313, 325, 328, and 332.  
     
     
         5 . An antibody according to  claim 1 , wherein said Fc variant comprises a substitution at position 332.  
     
     
         6 . An antibody according to  claim 1 , wherein at least one substitution is at a position selected from the group consisting of: 239, 264, 297, and 330, with the proviso that if said sequence is substantially human, said substitution is not S239A, V264A, N297A, N297Q, A330D, A330Q, A330K, or A330S.  
     
     
         7 . An antibody according to  claim 1 , wherein said Fc variant comprises at least one substitution selected from the group consisting of 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235D, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235F, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R, 243W, 243L 243Y, 243R, 243Q, 244H, 245A, 247V, 247G, 262I, 262A, 262T, 262E, 263I, 263A, 263T, 263M, 264L, 264I, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265G, 265N, 265Q, 265Y, 265F, 265V, 265I, 265L, 265H, 265T, 266I, 266A, 266T, 266M, 267L, 269H, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 296H, 297S, 297D, 297E, 298H, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 313F, 325Q, 325L, 325I, 325D, 325E, 325A, 325T, 325V, 325H, 327N, 327L, 328M, 328D, 328E, 328N, 328Q, 328F, 328I, 328V, 328T, 328H, 328A, 329F, 330L, 330Y, 330V, 330I, 330F, 330R, 330H, 332D, 332E, 332N, 332Q, 332T, 332H, 332Y, and 332A.  
     
     
         8 . An antibody according to  claim 1 , wherein said Fc variant is selected from the group consisting of 264L, 264I, 241W, 241L, 243W, 243L, 241L/243L/262I/264I, 241W/243W, 241W/243W/262A/264A, 241L/262I, 243L/264I, 243L/262I/264W, 241Y/243Y/262T/264T, 241E/243R/262E/264R, 241E/243Q/262T/264E, 241R/243Q/262T/264R, 241E/243Y/262T/264R, 328M, 328E, 328F, 332E, 328M/332E, 244H, 245A, 247V, 313F, 244H/245A/247V, 247G, 264I/332E, 241E/243R/262E/264R/332E, 241E/243Q/262T/264E/332E, 241R/243Q/262T/264R/332E, 241E/243Y/262T/264R/332E, 298A/332E, 239E/332E, 239Q/332E, 239E, 265G, 265N, 239E/265G, 239E/265N, 239E/265Q, 296E, 296Q, 299I, 327N, 267Q/327S, 267L/327S, 327L, 329F, 330L, 330Y, 332D, 297S, 297D, 297S/332E, 297D/332E, 297E/332E, 265Y/297D/332E, 265Y/297D/299L/332E, 265F/297E/332E, 328I/332E, 328Q/332E, 332N, 332Q, 264T, 264F, 240I, 263I, 266I, 299A, 299S, 299V, 325Q, 325L, 325I, 239D, 239N, 239F, 239D/332D, 239D/332E, 239D/332N, 239D/332Q, 239E/332D, 239E/332N, 239E/332Q, 239N/332D, 239N/332E, 239N/332N, 239N/332Q, 239Q/332D, 239Q/332N, 239Q/332Q, 296D, 296N, 241Y/243Y/262T/264T/297D/332E, 330Y/332E, 264I/330Y/332E, 330L/332E, 264I/330L/332E, 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235D, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235F, 239T, 239H, 239Y, 240A, 240T, 240M, 263A, 263T, 263M, 264M, 264Y, 266A, 266T, 266M, 269H, 269Y, 269F, 269R, 296S, 296T, 296L, 296I, 298H, 299H, 330V, 330I, 330F, 330R, 330H, 325D, 325E, 325A, 325T, 325V, 325H, 328D/332E, 328E/332E, 328N/332E, 328Q/332E, 328V/332E, 328T/332E, 328H/332E, 328I/332E, 328A, 332T, 332H, 332Y, 332A, 239E/264I/332E, 239Q/264I/332E, 239E/264I/330Y/332E, 239E/264I/298A/330Y/332E, 239D/297D/332E, 239E/297D/332E, 239D/265V/297D/332E, 239D/265I/297D/332E, 239D/265L/297D/332E, 239D/265F/297D/332E, 239D/265Y/297D/332E, 239D/265H/297D/332E, 239D/265T/297D/332E, 264E/297D/332E, 296D/297D/332E, 296E/297D/332E, 296N/297D/332E, 296Q/297D/332E, 296H/297D/332E, 296T/297D/332E, 297D/299V/332E, 297D/299I/332E, 297D/299L/332E, 297D/299F/332E, 297D/299H/332E, 297D/299E/332E, 297D/330Y/332E, 297D/298A/330Y/332E, 239D/330Y/332E, 239N/330Y/332E, 239D/330L/332E, 239N/330L/332E, 264I/298A/332E, 239D/298A/332E, 239N/298A/332E, 239D/264I/332E, 239D/264I/298A/332E, and 239D/264I/330L/332E.  
     
     
         9 . An antibody according to  claim 7 , wherein said Fc variant portion further comprises at least one substitution at a position corresponding to a position of the human sequence selected from the group consisting of: 256, 270, 290, 298, 312, 322, 326, 329, 331, 333, 334, and 339.  
     
     
         10 . An antibody according to  claim 1 , wherein said FcγR is FcγRIIa.  
     
     
         11 . An antibody according to  claim 10 , wherein said FcγRIIIa is a V158 or F158 allotype of FcγRIIIa.  
     
     
         12 . An Fc variant according to  claim 2 , wherein said parent Fc polypeptide is substantially human, and said affinity is approximately 5-fold greater than that of said parent Fc polypeptide.  
     
     
         13 . An antibody according to  claim 12 , wherein said parent Fc polypeptide is substantially human, and said affinity is between about 5-fold and about 300-fold greater than that of said parent Fc polypeptide.  
     
     
         14 . An antibody according to  claim 12 , wherein said Fc variant portion comprises at least one substitution at a position corresponding to a position of the human sequence selected from the group consisting 234, 235, 239, 240, 243, 264, 266, 328, 330, 332, and 325.  
     
     
         15 . An antibody according to  claim 14 , wherein said Fc variant comprises at least one substitution selected from the group consisting of 234E, 234Y, 234I, 235D, 235S, 235Y, 235I, 239D, 239E, 239N, 239Q, 239T, 240I, 240M, 243L, 264I, 264T, 264Y, 266I, 328M, 328I, 328Q, 328D, 328V, 328T, 330Y, 330L, 330I, 332D, 332E, 332N, 332Q, and 325T.  
     
     
         16 . An antibody according to  claim 15 , wherein said Fc variant is selected from the group consisting of 264I, 243L/264I, 328M, 332E, 328M/332E, 264I/332E, 298A/332E, 239E/332E, 239Q/332E, 239E, 330Y, 332D, 328I/332E, 328Q/332E, 264T, 240I, 266I, 239D, 239D/332D, 239D/332E, 239D/332N, 239D/332Q, 239E/332D, 239E/332N, 239E/332Q, 239N/332D, 239N/332E, 239Q/332D, 330Y/332E, 264I/330Y/332E, 330L/332E, 264I/330L/332E, 234E, 234Y, 234I, 235D, 235S, 235Y, 235I, 239T, 240M, 264Y, 330I, 325T, 328D/332E, 328V/332E, 328T/332E, 328I/332E, 239E/264I/332E, 239Q/264I/332E, 239E/264I/330Y/332E, 239D/330Y/332E, 239N/330Y/332E, 239D/330L/332E, 239N/330L/332E, 264I/298A/332E, 239D/298A/332E, 239N/298A/332E, 239D/264I/332E, 239D/264I/298A/332E, and 239D/264I/330L/332E.  
     
     
         17 . An antibody according to  claim 15 , wherein said Fc variant further comprises at least one substitution at a position selected from the group consisting of 256, 270, 290, 298, 312, 322, 326, 329, 331, 333, 334, and 339.  
     
     
         18 . An antibody according to  claim 1  or  2 , wherein said parent Fc polypeptide is substantially human, substantially mouse, substantially rat, or substantially monkey.  
     
     
         19 . An antibody according to  claim 1  or  2 , wherein binding to one or more Fc ligands is unaltered.  
     
     
         20 . An antibody according to  claim 19 , wherein said Fc ligand is selected from the group consisting of C1q, FcRn, protein A, and protein G.  
     
     
         21 . An antibody according to  claim 1  or  2 , wherein CDC is unaffected.  
     
     
         22 . An antibody according to  claim 1  or  2 , wherein binding to one or more Fc ligands is altered.  
     
     
         23 . An antibody according to  claim 1 , wherein said Fc variant has a FcγRIIIa-fold:FcγRIIb-fold ratio greater than 1.  
     
     
         24 . An antibody according to  claim 23 , wherein said Fc variant has a FcγRIIIa-fold:FcγRIIb-fold ratio greater than approximately 11:1.  
     
     
         25 . An antibody according to  claim 24 , wherein said Fc variant has a FcγRIIIa-fold:FcγRIIb-fold ratio between approximately 11:1 and approximately 86:1.  
     
     
         26 . An antibody according to  claim 23 , wherein said Fc variant portion comprises at least one substitution at a position corresponding to a position of the human sequence selected from the group consisting of: 234, 235, 239, 240, 264, 296, 330, and I332.  
     
     
         27 . An antibody according to  claim 26 , wherein said Fc variant comprises at least one substitution selected from the group consisting of: 234Y, 234I, 235I, 239D, 239E, 239N, 239Q, 240A, 240M, 264I, 264Y, 296Q, 330L, 330Y, 330I, 332D, and 332E.  
     
     
         28 . An antibody according to  claim 27 , wherein said Fc variant is selected from the group consisting of 332E, 264I/332E, 239E/332E, 239Q/332E, 296Q, 330L, 330Y, 332D, 239D, 239D/332E, 330Y/332E, 264I/330Y/332E, 330L/332E, 264I/330L/332E, 234Y, 234I, 235I, 240A, 240M, 264Y, 330I, 239D/330L/332E, 239D/298A/332E, 239N/298A/332E, 239D/264I/332E, 239D/264I/298A/332E, and 239D/264I/330L/332E.  
     
     
         29 . An antibody according to  claim 26 , wherein said Fc variant further comprises one or more substitutions at a position selected from the group consisting of 256, 270, 290, 298, 312, 322, 326, 329, 331, 333, 334, and 339.  
     
     
         30 . An antibody according to  claim 1 , wherein said Fc variant binds to at least one FcγR with reduced affinity relative to the parent Fc polypeptide.  
     
     
         31 . An antibody according to  claim 30 , wherein said FcγR is FcγRIIIa.  
     
     
         32 . An antibody according to  claim 31 , wherein said Fc variant comprises at least one substitution selected from the group consisting of 234D, 234N, 234Q, 234T, 234H, 234V, 234F, 235N, 235Q, 235T, 235H, 235V, 235F, 239E, 239N, 239Q, 239F, 239H, 239Y, 240A, 240T, 241W, 241L, 241Y, 241E, 241R, 243W, 243L 243Y, 243R, 243Q, 244H, 245A, 247V, 247G, 262I, 262A, 262T, 262E, 263I, 263A, 263T, 263M, 264L, 264I, 264W, 264T, 264R, 264F, 264M, 264E, 265G, 265N, 265Q, 265Y, 265F, 265V, 265I, 265L, 265H, 265T, 266A, 266T, 266M, 267Q, 267L, 269H, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 296H, 297S, 297D, 297E, 298H, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 313F, 325Q, 325L, 325I, 325D, 325E, 325A, 325V, 325H, 327N, 327L, 328M, 328E, 328N, 328Q, 328F, 328H, 328A, 329F, 330L, 330V, 330F, 330R, 330H, 332N, 332Q, 332T, 332H, 332Y, and 332A  
     
     
         33 . An antibody according to  claim 31 , wherein said Fc variant is selected from the group consisting of 264L, 241W, 241L, 243W, 243L, 241L/243L/262I/264I, 241W/243W, 241W/243W/262A/264A, 241L/262I, 243L/262I/264W, 241Y/243Y/262T/264T, 241E/243R/262E/264R, 241E/243Q/262T/264E, 241R/243Q/262T/264R, 241E/243Y/262T/264R, 328M, 328E, 328F, 244H, 245A, 247V, 313F, 244H/245A/247V, 247G, 241E/243R/262E/264R/332E, 241E/243Y/262T/264R/332E, 265G, 265N, 239E/265G, 239E/265N, 239E/265Q, 296E, 296Q, 299I, 327N, 267Q/327S, 267L/327S, 327L, 329F, 330L, 297S, 297D, 297S/332E, 332N, 332Q, 264F, 263I, 299A, 299S, 299V, 325Q, 325L, 325I, 239N, 239F, 239N/332N, 239N/332Q, 239Q/332N, 239Q/332Q, 296D, 296N, 234D, 234N, 234Q, 234T, 234H, 234V, 234F, 235N, 235Q, 235T, 235H, 235V, 235F, 239H, 239Y, 240A, 263T, 263M, 264M, 266A, 266T, 266M, 269H, 269Y, 269F, 269R, 296S, 296T, 296L, 296I, 298H, 299H, 330V, 330F, 330R, 330H, 325D, 325E, 325A, 325V, 325H, 328E/332E, 328N/332E, 328Q/332E, 328H/332E, 328A, 332T, 332H, 332Y, and 332A.  
     
     
         34 . An antibody comprising a variant of a parent Fc polypeptide comprising at least one amino acid modification in the Fc region of said parent Fc polypeptide, wherein said Fc variant modulates effector function as compared to the parent Fc polypeptide.  
     
     
         35 . An antibody according to  claim 34 , wherein said effector function is ADCC.  
     
     
         36 . An antibody according to  claim 35 , wherein said Fc variant improves ADCC as compared to said parent Fc polypeptide.  
     
     
         37 . An antibody according to  claim 36 , wherein said ADCC improvement is approximately 5-fold greater than that of said parent Fc polypeptide.  
     
     
         38 . An antibody according to  claim 37 , wherein said ADCC improvement is between approximately 5-fold and 50-fold greater than that of said parent Fc polypeptide.  
     
     
         39 . An antibody according to  claim 37 , wherein said Fc variant portion comprises at least one substitution at a position corresponding to a position of the human sequence selected from the group consisting of: 234, 235, 239, 240, 243, 264, 266, 328, 330, 332, and 325.  
     
     
         40 . An antibody according to  claim 39 , wherein said Fc variant comprises at least one substitution selected from the group consisting of 234E, 234Y, 234I, 235D, 235S, 235Y, 235I, 239D, 239E, 239N, 239Q, 239T, 240I, 240M, 243L, 264I, 264T, 264Y, 266I, 328M, 328I, 328Q, 328D, 328V, 328T, 330Y, 330L, 330I, 332D, 332E, 332N, 332Q, and 325T.  
     
     
         41 . An antibody according to  claim 39 , wherein said Fc variant is selected from the group consisting of 264I, 243L/264I, 328M, 332E, 328M/332E, 264I/332E, 298A/332E, 239E/332E, 239Q/332E, 239E, 330Y, 332D, 328I/332E, 328Q/332E, 264T, 240I, 266I, 239D, 239D/332D, 239D/332E, 239D/332N, 239D/332Q, 239E/332D, 239E/332N, 239E/332Q, 239N/332D, 239N/332E, 239Q/332D, 330Y/332E, 264I/330Y/332E, 330L/332E, 264I/330L/332E, 234E, 234Y, 234I, 235D, 235S, 235Y, 235I, 239T, 240M, 264Y, 330I, 325T, 328D/332E, 328V/332E, 328T/332E, 328I/332E, 239E/264I/332E, 239Q/264I/332E, 239E/264I/330Y/332E, 239D/330Y/332E, 239N/330Y/332E, 239D/330L/332E, 239N/330L/332E, 264I/298A/332E, 239D/298A/332E, 239N/298A/332E, 239D/264I/332E, 239D/264I/298A/332E, and 239D/264I/330L/332E.  
     
     
         42 . An antibody according to  claim 39 , wherein said Fc variant further comprises at least one substitution at a position selected from the group consisting of 256, 270, 290, 298, 312, 322, 326, 329, 331, 333, 334, and 339.  
     
     
         43 . An antibody according to  claim 39 , wherein said parent Fc polypeptide is substantially human, substantially mouse, substantially rat, or substantially monkey.  
     
     
         44 . An antibody according to  claim 35 , wherein said Fc variant reduces ADCC as compared to said parent Fc polypeptide.  
     
     
         45 . An antibody according to  claim 44 , wherein said Fc variant comprises at least one substitution selected from the group consisting of 234D, 234N, 234Q, 234T, 234H, 234V, 234F, 235N, 235Q, 235T, 235H, 235V, 235F, 239E, 239N, 239Q, 239F, 239H, 239Y, 240A, 240T, 241W, 241L, 241Y, 241E, 241R, 243W, 243L 243Y, 243R, 243Q, 244H, 245A, 247V, 247G, 262I, 262A, 262T, 262E, 263I, 263A, 263T, 263M, 264L, 264I, 264W, 264T, 264R, 264F, 264M, 264E, 265G, 265N, 265Q, 265Y, 265F, 265V, 265I, 265L, 265H, 265T, 266A, 266T, 266M, 267Q, 267L, 269H, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 296H, 297S, 297D, 297E, 298H, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 313F, 325Q, 325L, 325I, 325D, 325E, 325A, 325V, 325H, 327N, 327L, 328M, 328E, 328N, 328Q, 328F, 328H, 328A, 329F, 330L, 330V, 330F, 330R, 330H, 332N, 332Q, 332T, 332H, 332Y, and 332A.  
     
     
         46 . An antibody according to  claim 44 , wherein said Fc variant is selected from the group consisting of 264L, 241W, 241L, 243W, 243L, 241L/243L/262I/264I, 241W/243W, 241W/243W/262A/264A, 241L/262I, 243L/262I/264W, 241Y/243Y/262T/264T, 241E/243R/262E/264R, 241E/243Q/262T/264E, 241R/243Q/262T/264R, 241E/243Y/262T/264R, 328M, 328E, 328F, 244H, 245A, 247V, 313F, 244H/245A/247V, 247G, 241E/243R/262E/264R/332E, 241E/243Y/262T/264R/332E, 265G, 265N, 239E/265G, 239E/265N, 239E/265Q, 296E, 296Q, 299I, 327N, 267Q/327S, 267L/327S, 327L, 329F, 330L, 297S, 297D, 297S/332E, 332N, 332Q, 264F, 263I, 299A, 299S, 299V, 325Q, 325L, 325I, 239N, 239F, 239N/332N, 239N/332Q, 239Q/332N, 239Q/332Q, 296D, 296N, 234D, 234N, 234Q, 234T, 234H, 234V, 234F, 235N, 235Q, 235T, 235H, 235V, 235F, 239H, 239Y, 240A, 263T, 263M, 264M, 266A, 266T, 266M, 269H, 269Y, 269F, 269R, 296S, 296T, 296L, 296I, 298H, 299H, 330V, 330F, 330R, 330H, 325D, 325E, 325A, 325V, 325H, 328E/332E, 328N/332E, 328Q/332E, 328H/332E, 328A, 332T, 332H, 332Y, and 332A.  
     
     
         47 . An antibody comprising an aglycosylated Fc variant of a parent Fc polypeptide comprising at least one amino acid modification in the Fc region of said parent Fc polypeptide, wherein said aglycosylated Fc variant has improved stability, solubility, or binding affinity to an Fc ligand relative to the aglycosylated form of said parent Fc polypeptide.  
     
     
         48 . An antibody according to  claim 47 , wherein said aglycosylated Fc variant has improved binding affinity to an Fc ligand as compared to the aglycosylated form of the parent Fc polypeptide.  
     
     
         49 . An antibody according to  claim 48 , wherein said Fc ligand is an FcγR.  
     
     
         50 . An antibody according to  claim 49 , wherein said FcγR is FcγRIIa.  
     
     
         51 . An antibody according to  claim 48 , wherein said improved binding affinity is within 0.4-fold of the glycosylated form of the parent Fc polypeptide.  
     
     
         52 . An antibody according to  claim 47 , wherein said Fc variant portion comprises at least one substitution at a position corresponding to a position of the human sequence selected from the group consisting of: 239, 241, 243, 262, 264, 265, 296, 297, 330, and 332.  
     
     
         53 . An antibody according to  claim 52 , wherein said Fc variant comprises one or more substitutions selected from the group consisting of 239D, 239E, 241Y, 243Y, 262T, 264T, 264E, 265Y, 265H, 296N, 297D, 330Y, and 332E.  
     
     
         54 . An antibody according to  claim 52 , wherein said Fc variant is selected from the group consisting of 297D/332E, 241Y/243Y/262T/264T/297D/332E, 239D/297D/332E, 239E/297D/332E, 239D/265Y/297D/332E, 239D/265H/297D/332E, 264E/297D/332E, 296N/297D/332E, and 297D/330Y/332E.  
     
     
         55 . An antibody according to  claim 53 , wherein said aglycosylated Fc variant portion comprises at least one substitution at a position corresponding to a position of the human sequence selected from the group consisting of: 256, 270, 290, 298, 312, 322, 326, 329, 331, 333, 334, and 339.  
     
     
         56 . An antibody according to  claim 1  comprising a Fc fusion comprising said Fc variant.  
     
     
         57 . An antibody according to  claim 1  or  56 , wherein said antibody further comprises an engineered glycoform.  
     
     
         58 . An antibody according to  claim 57 , wherein said engineered glycoform improves effector function.  
     
     
         59 . A pharmaceutical composition comprising an antibody according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         60 . A method of treating a mammal in need of said treatment, comprising administering an antibody of  claim 1 .  
     
     
         61 . An antibody comprising an Fc variant, said Fc variant comprises at least one substitution selected from the group consisting of: 332D, 332E, 332N, or 332Q, wherein said positions corresponding to the human sequence position, wherein said antibody has specificity for a target antigen selected from the group consisting of CD20, CD22, CD33, CD52, Her2/neu, EGFR, EpCAM, MUCd, GD3, CEA, CA 125, HLA-DR, TNFalpha, and VEGF.  
     
     
         62 . An antibody comprising an Fc variant, said Fc variant comprises at least one substitution selected from the group consisting of 264I, 264T, or 264Y, wherein said positions corresponding to the human sequence position, wherein said antibody or Fc fusion has specificity for a target antigen selected from the group consisting of CD20, CD22, CD33, CD52, Her2/neu, EGFR, EpCAM, MUC1, GD3, CEA, CA 125, HLA-DR, TNFalpha, and VEGF.  
     
     
         63 . An antibody comprising an Fc variant, said Fc variant comprises at least one substitution selected from the group consisting of 239D, 239E, 239N, 239Q, or 239T, wherein said positions corresponding to the human sequence position, wherein said antibody or Fc fusion has specificity for a target antigen selected from the group consisting of CD20, CD22, CD33, CD52, Her2/neu, EGFR, EpCAM, MUC1, GD3, CEA, CA 125, HLA-DR, TNFalpha, and VEGF.  
     
     
         64 . An antibody comprising an Fc variant, said Fc variant comprises at least one substitution selected from the group consisting of 330Y, 330L, or 330I, wherein said positions corresponding to the human sequence position, wherein said antibody or Fc fusion has specificity for a target antigen selected from the group consisting of CD20, CD22, CD33, CD52, Her2/neu, EGFR, EpCAM, MUC1, GD3, CEA, CA 125, HLA-DR, TNFalpha, and VEGF.  
     
     
         65 . An antibody comprising an Fc variant, said Fc variant comprises at least one substitution selected from the group consisting of 240I or 240M, wherein said positions corresponding to the human sequence position, wherein said antibody or Fc fusion has specificity for a target antigen selected from the group consisting of CD20, CD22, CD33, CD52, Her2/neu, EGFR, EpCAM, MUC1, GD3, CEA, CA 125, HLA-DR, TNFalpha, and VEGF.  
     
     
         66 . An antibody comprising an Fc variant, said Fc variant comprises a substitution consisting of 297D, wherein said position corresponds to the human sequence position, wherein said antibody or Fc fusion has specificity for a target antigen selected from the group consisting of CD20, CD22, CD33, CD52, Her2/neu, EGFR, EpCAM, MUC1, GD3, CEA, CA 125, HLA-DR, TNFalpha, and VEGF.  
     
     
         67 . An antibody according to claims  61 ,  62 ,  63 ,  64 ,  65  or  66  wherein said Fc variant additionally comprises the substitutions 298A.
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