Fc VARIANTS

Abstract

Disclosed are Fc-containing proteins comprising a binding region and a variant Fc region that can elicit one or more immune effector function and/or bind to an Fc receptor more effectively than a similar Fc-containing protein comprising a wild type Fc region. Also disclosed are nucleic acids encoding such Fc-containing proteins, methods for making such proteins, and methods of treatment utilizing such proteins.

What is claimed is: 
     
         1 - 52 . (canceled) 
     
     
         53 . An Fc-containing protein comprising a heterodimeric human IgG Fc region and a binding region, wherein the Fc region comprises an A chain and a B chain, which each comprise from 1 to 10 amino acid substitutions relative to a wild type human Fc polypeptide chain, wherein the Fc-containing protein binds to human FcγRIIIA-158F and/or FcγRIIIA-158V with a K D  of less than or equal to one fifth of the K D  with which a second protein binds to human FcγRIIIA-158F and/or FcγRIIIA-158V, wherein the second protein is the same as the Fc-containing protein except that it contains a wild type human IgG Fc region without substitutions. 
     
     
         54 . The Fc-containing protein of  claim 53 , wherein the Fc-containing protein binds to human FcγRIIIA-158F and/or FcγRIIIA-158V with a K D  of less than or equal to one tenth of the K D  with which the second protein binds to human FcγRIIIA-158F and/or FcγRIIIA-158V. 
     
     
         55 . The Fc-containing protein of  claim 53 , wherein the A chain and the B chain each comprise from 1 to 6 amino acid substitutions relative to a wild type human Fc polypeptide chain. 
     
     
         56 . The Fc-containing protein of  claim 53 , which comprises charge pair substitutions. 
     
     
         57 . The Fc-containing protein of  claim 56 , wherein the A chain comprises the substitutions K392D and K409D and the B chain comprises the substitutions E356K and D399K or vice versa. 
     
     
         58 . The Fc-containing protein of  claim 53 , wherein the IgG Fc region is an IgG1 Fc region. 
     
     
         59 . The Fc-containing protein of  claim 53 , wherein
 (a) the A chain comprises Q311M and K334V substitutions and the B chain comprises L234Y, E294L, and Y296W substitutions or vice versa;   (b) the A chain comprises E233L, Q311M, and K334V substitutions and the B chain comprises L234Y, E294L, and Y296W substitutions;   (c) the A chain comprises L234I, Q311M, and K334V substitutions and the B chain comprises L234Y, E294L, and Y296W substitutions or vice versa;   (d) the A chain comprises S298T and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (e) the A chain comprises A330M and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (f) the A chain comprises A330F and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (g) the A chain comprises Q311M, A330M, and K334V substitutions and the B chain comprises L234Y, E294L, and Y296W substitutions or vice versa;   (h) the A chain comprises Q311M, A330F, and K334V substitutions and the B chain comprises L234Y, E294L, and Y296W substitutions or vice versa;   (i) the A chain comprises S298T, A330M, and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (j) the A chain comprises S298T, A330F, and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (k) the A chain comprises S239D, A330M, and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (l) the A chain comprises S239D, S298T, and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (m) the A chain comprises a K334V substitution and the B chain comprises Y296W and S298C substitutions or vice versa;   (n) the A chain comprises a K334V substitution and the B chain comprises L234Y, Y296W, and S298C substitutions or vice versa;   (o) the A chain comprises L235S, S239D, and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (p) the A chain comprises L235S, S239D, and K334V substitutions and the B chain comprises L234Y, Y296W, and S298C substitutions or vice versa;   (q) the A chain comprises Q311M and K334V substitutions and the B chain comprises L234Y, F243V, and Y296W substitutions or vice versa;   (r) the A chain comprises Q311M and K334V substitutions and the B chain comprises L234Y, K296W, and S298C substitutions or vice versa;   (s) the A chain comprises S239D and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (t) the A chain comprises S239D and K334V substitutions and the B chain comprises L234Y, Y296W, and S298C substitutions or vice versa;   (u) the A chain comprises F243V and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W, substitutions or vice versa;   (v) the A chain comprises F243V and K334V substitutions and the B chain comprises L234Y, Y296W, and S298C substitutions or vice versa;   (w) the A chain comprises E294L and K334V substitutions and the B chain comprises L234Y, K290Y, and Y296W substitutions or vice versa;   (x) the A chain comprises E294L and K334V substitutions and the B chain comprises L234Y, Y296W, and S298C substitutions or vice versa;   (y) the A chain comprises A330M and K334V substitutions and the B chain comprises L234Y and Y296W substitutions or vice versa; or   (z) the A chain comprises A330M and K334V substitutions and the B chain comprises K290Y and Y296W substitutions or vice versa.   
     
     
         60 . The Fc-containing protein of  claim 59 , wherein the A chain comprises the amino acid sequence of SEQ ID NO: 8, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, or 37 and the B chain comprises the amino acid sequence of SEQ ID NO: 10, 18, 39, or 41. 
     
     
         61 . The Fc-containing protein of  claim 60  comprising a pair of amino acid sequences selected from the group consisting of: SEQ ID NO: 8 and SEQ ID NO:10; SEQ ID NO: 16 and SEQ ID NO:18; SEQ ID NO: 12 and SEQ ID NO:10; SEQ ID NO: 14 and SEQ ID NO:10; SEQ ID NO: 20 and SEQ ID NO:18; SEQ ID NO: 22 and SEQ ID NO:18; SEQ ID NO: 24 and SEQ ID NO:10; SEQ ID NO: 26 and SEQ ID NO:10; SEQ ID NO: 28 and SEQ ID NO:18; SEQ ID NO: 30 and SEQ ID NO:18; SEQ ID NO: 32 and SEQ ID NO:18; SEQ ID NO: 34 and SEQ ID NO:18; SEQ NO:37 and SEQ ID NO:39; and SEQ NO:37 and SEQ ID NO:41. 
     
     
         62 . The Fc-containing protein of  claim 53 , wherein:
 the Fc-containing protein is defucosylated, is made in a CHO cell, and/or is an antibody; or   the Fc-containing protein is defucosylated, is made in a CHO cell, and/or is an Fc fusion protein.   
     
     
         63 . The Fc-containing protein of  claim 62 , wherein the Fc-containing protein is an antibody and wherein the antibody is bispecific and/or is a full length human IgG1 antibody. 
     
     
         64 . The Fc-containing protein of  claim 53 , wherein the Fc-containing protein binds to HER-2/neu, wherein the Fc-containing protein is a bispecific antibody that binds to CD38 and CD138, or wherein the Fc-containing protein binds to mesothelin. 
     
     
         65 . A pharmaceutical composition comprising a therapeutically effective amount of the Fc-containing protein of  claim 53  and a pharmaceutically acceptable carrier. 
     
     
         66 . One or more nucleic acids encoding the Fc-containing protein of  claim 53 . 
     
     
         67 . The one or more nucleic acids of  claim 66 , which comprise the nucleotide sequences of SEQ ID NO: 7, 11, 13, 15, 19, 21, 23, 25, 27, 29, 31, 33, or 36 and SEQ ID NO:9, 17, 38, or 40. 
     
     
         68 . A host cell comprising the one or more nucleic acids of  claim 66 . 
     
     
         69 . The host cell of  claim 68 , which is a CHO cell. 
     
     
         70 . A method of making an Fc-containing protein containing a heterodimeric Fc region comprising the following steps:
 (a) providing a host cell containing one or more nucleic acids encoding an Fc-containing protein comprising a heterodimeric human IgG Fc region and a binding region, wherein the Fc region comprises an A chain and a B chain, which each comprise from 1 to 10 amino acid substitutions relative to a wild type human Fc polypeptide chain, wherein the Fc-containing protein binds to human FcγRIIIA-158F and/or FcγRIIIA-158V with a K D  of less than or equal to one fifth of the K D  with which a second protein binds to human FcγRIIIA-158F and/or FcγRIIIA-158V, wherein the second protein is the same as the Fc-containing protein except that it contains a wild type human IgG Fc region without substitutions;   (b) culturing the host cell under conditions such that the Fc-containing protein will be expressed; and   (c) recovering the Fc-containing protein from the cell mass or the culture medium.   
     
     
         71 . A method for treating cancer comprising administering an Fc-containing protein or pharmaceutical composition comprising the Fc-containing protein to a cancer patient, wherein the Fc-containing protein comprises a heterodimeric human IgG Fc region and a binding region, wherein the Fc region comprises an A chain and a B chain, which each comprise from 1 to 10 amino acid substitutions relative to a wild type human Fc polypeptide chain, wherein the Fc-containing protein binds to human FcγRIIIA-158F and/or FcγRIIIA-158V with a K D  of less than or equal to one fifth of the K D  with which a second protein binds to human FcγRIIIA-158F and/or FcγRIIIA-158V, wherein the second protein is the same as the Fc-containing protein except that it contains a wild type human IgG Fc region without substitutions. 
     
     
         72 . The method of  claim 71 , wherein chemotherapy and/or radiation is administered before, after, or concurrently with the administration of the Fc-containing protein.