Modified antibody constant regions
The present inventors successfully provided constant regions capable of enhancing the agonist activity of antibodies through amino acid sequence alterations. Specifically, agonist activity was found to be enhanced in antibodies having a constant region in which amino acids of the antibody heavy chain constant region are substituted or deleted, or antibodies having a constant region in which the hinge region amino acids are substituted. Use of such antibodies as pharmaceutical formulations can provide pharmaceutical formulations with improved performance.
1. An antibody comprising a heavy chain and a light chain that together comprise a Fab fragment that binds to a target antigen, wherein the antibody agonizes the target antigen, and wherein the heavy chain comprises a constant region that comprises the amino acid sequence of SEQ ID NO: 32 with only the following mutations, wherein all positions are identified by EU numbering:
(a) deletion of the amino acid residues at positions 222, 223, 224, and 225; and
(b) optionally, one of the following (1) to (3):
(1) substitution of the amino acid residues at positions 219 and 220 with Cys and Ser, respectively;
(2) substitution of the amino acid residues at positions 219, 220, and 221 with Cys, Ser, and Val, respectively; or
(3) substitution of the amino acid residues at positions 192, 193, 199, 214, 217, 219, 220, and 221 with Asn, Phe, Thr, Thr, Arg, Cys, Ser, and Val, respectively.
2. The antibody of claim 1 , wherein the heavy chain comprises a constant region that comprises the amino acid sequence of SEQ ID NO: 32 with only the following mutations, wherein all positions are identified by EU numbering:
(a) deletion of the amino acid residues at positions 222, 223, 224, and 225.
3. The antibody of claim 1 , wherein the mutations include substitution of the amino acid residues at EU numbering positions 219 and 220 with Cys and Ser, respectively.
4. The antibody of claim 1 , wherein the mutations include substitution of the amino acid residues at EU numbering positions 219, 220, and 221 with Cys, Ser, and Val, respectively.
5. The antibody of claim 1 , wherein the mutations include substitution of the amino acid residues at EU numbering positions 192, 193, 199, 214, 217, 219, 220, and 221 with Asn, Phe, Thr, Thr, Arg, Cys, Ser, and Val, respectively.