Bispecific Asymmetric Heterodimers Comprising Anti-CD3 Constructs
Disclosed herein are isolated multi-specific heteromultimer constructs that bind to CD3 expressed on T-cells and to an antigen expressed on B-cells. The multi-specific heteromultimer constructs are capable of bridging T- and B-cells and mediating killing of B-cells. The multi-specific heteromultimer constructs are based on a heterodimeric Fc scaffold or on a segmented albumin scaffold. Also disclosed herein are multi-specific heteromultimer constructs that bind to HER2 and HER3.
1 . An isolated polypeptide comprising an Fc variant of a wild-type human IgG Fc, the Fc variant comprising a L234A amino acid substitution, a L235A amino acid substitution, and a D265S amino acid substitution, wherein the amino acid positions are numbered according to the EU index of Kabat.
2 . The polypeptide of claim 1 , wherein the polypeptide further comprises at least one antigen-binding domain.
3 . The polypeptide of claim 2 , wherein the antigen-binding domain comprises an scFv.
4 . The polypeptide of claim 2 , wherein the antigen-binding domain comprises a Fab.
5 . The polypeptide of claim 1 , wherein the polypeptide further comprises an scFv and a Fab.
6 . The polypeptide of claim 1 , wherein the Fc variant further comprises amino acid substitutions T350V, L351Y, F405A, and Y407V, wherein the amino acid positions are numbered according to the EU index of Kabat.
7 . The polypeptide of claim 1 , wherein the Fc variant further comprises amino acid substitutions T350V, T366L, K392L, and T394W, wherein the amino acid positions are numbered according to the EU index of Kabat.
8 . The polypeptide of claim 1 , wherein the IgG is an IgG1.
9 . The polypeptide of claim 1 , wherein the polypeptide comprises an antibody or an Fc fusion.
10 . An antibody comprising the polypeptide of claim 1 .
11 . The antibody of claim 10 , wherein the antibody is a monoclonal antibody, a humanized antibody, or a human antibody.
12 . The antibody of claim 10 , wherein the antibody is multispecific.
13 . The antibody of claim 10 , wherein the antibody is bispecific.
14 . A dimer comprising the polypeptide of claim 1 .
15 . A heterodimer comprising the polypeptide of claim 1 .
16 . A pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier.
17 . A pharmaceutical composition comprising the antibody of claim 10 and a pharmaceutically acceptable carrier.
18 . An isolated nucleotide sequence encoding the polypeptide of claim 1 .
19 . A vector comprising the nucleotide sequence of claim 18 .
20 . A host cell comprising the vector of claim 19 .
21 . A method of producing a polypeptide, comprising culturing the host cell of claim 20 , and producing the polypeptide.