Method of treating cancer comprising administration of anti-HER2 antibody-drug conjugate
As an antitumor drug which is excellent in terms of antitumor effect and safety and has an excellent therapeutic effect, there is provided an antibody-drug conjugate in which an antitumor compound represented by the following formula is conjugated to an anti-HER2 antibody via a linker having a structure represented by the following formula: -L 1 -L 2 -L P -NH—(CH 2 )n 1 -L a -(CH 2 )n 2 -C(═O)— wherein the anti-HER2 antibody is connected to the terminal L 1 , and the antitumor compound is connected to the carbonyl group of the —(CH 2 )n 2 -C(═O)— moiety with the nitrogen atom of the amino group at position 1 as the connecting position.
1. A method for producing an anti-HER2 antibody-drug conjugate or a salt thereof, comprising:
treating an anti-HER2 antibody in a reducing condition and thereafter reacting the anti-HER2 antibody with a compound represented by the following formula:
(maleimid-N-yl)-CH 2 CH 2 CH 2 CH 2 CH 2 -C(═O)-GGFG (SEQ ID NO: 3)-NH-CH 2 -O-CH 2 -C(═O)—(NH-DX),
wherein (maleimid-N-yl)- is a group represented by the following formula:
wherein the nitrogen atom is a connecting position;
and wherein (NH-DX) represents a group represented by the following formula:
wherein the nitrogen atom of the amino group at position 1 is the connecting position.
2. The method of claim 1 , wherein the antibody-drug conjugate comprises a linker and an antitumor compound represented by the following formula and anti-HER2 antibody connected to the linker:
-(Succinimid-3-yl-N)-CH 2 CH 2 CH 2 CH 2 CH 2 -C(═O)-GGFG (SEQ ID NO: 3)-NH-CH 2 -O—CH 2 —C(═O)—(NH-DX)
wherein
-(Succinimid-3-yl-N)- has a structure represented by the following formula:
which is connected to the antibody at position 3 thereof and is connected to a methylene group in the linker structure containing this structure on the nitrogen atom at position 1, and
(NH-DX) represents a group represented by the following formula:
wherein the nitrogen atom of the amino group at position 1 is the connecting position.
3. The method of claim 1 , wherein the anti-HER2 antibody comprises a heavy chain and a light chain selected from the group:
a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2, and
a heavy chain consisting of the amino acid sequence of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence of SEQ ID NO: 2.
4. The method of claim 1 , wherein the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.
5. The method of claim 1 , wherein the anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence of SEQ ID NO: 2.
6. The method of claim 1 , wherein the average number of units of the drug-linker moiety conjugated per antibody molecule is in the range of from 2 to 8.
7. The method of claim 1 , wherein the average number of units of the drug-linker moiety conjugated per antibody molecule is in the range of from 3 to 8.