Sensitivity marker for antibody-drug conjugate

Patent metadata

Field	Value
Publication number	US-12312641-B2
Application number	US-201917269615-A
Country	US
Kind code	B2
Filing date	Aug 22, 2019
Priority date	Aug 23, 2018
Publication date	May 27, 2025
Grant date	May 27, 2025

Abstract

A method for identifying a subject to whom a medicament containing an anti-hTROP2 antibody is to be given, wherein the subject is a human patient suffering from a cancer, comprising: obtaining a biological sample from the human patient diagnosed as suffering from a cancer; evaluating an amount of expression of the hTROP2 gene at mRNA level in the biological sample; evaluating an amount of expression of the SLFN11 gene at mRNA level in the biological sample, wherein the biological sample is one that is determined to have a high amount of expression of the hTROP2 gene; and identifying the human patient who provided the biological sample, wherein the biological sample is one that is determined to have a high amount of expression of the SLFN11 gene, as a subject to whom a medicament containing an anti-hTROP2 antibody is to be given.

First claim

The invention claimed is:

1. A method for identifying a subject to whom a medicament containing an anti-hTROP2 antibody-drug conjugate is to be given, wherein the subject is a human patient suffering from a cancer, the method comprising:
1) obtaining a biological sample from the human patient diagnosed as suffering from a cancer;
2) evaluating an amount of expression of the hTROP2 gene at mRNA level in the biological sample;
3) evaluating an amount of expression of the SLFN11 gene at mRNA level in the biological sample, wherein the biological sample is one that is determined to have a high amount of expression of the hTROP2 gene; and
4) identifying the human patient who provided the biological sample, wherein the biological sample is one that is determined to have a high amount of expression of the SLFN11 gene, as a subject to whom an anti-hTROP2 antibody-drug conjugate is to be given,
wherein the drug portion of the anti-hTROP2 antibody-drug conjugate comprises a topoisomerase I inhibitor,
wherein a log 2 [FPKM+1] value is measured by RNA sequencing from the biological sample obtained from the human patient diagnosed as suffering from a cancer,
wherein the biological sample is determined to have a high amount of expression of the hTROP2 gene at mRNA level when the log 2 [FPKM+1] value exceeds 6.0,
wherein the biological sample is determined to have a high amount of expression of the SLFN11 gene at mRNA level when the log 2 [FPKM+1] value exceeds 2.0, and
the subject identified in step 4) is treated with the anti-hTROP2 antibody-drug conjugate.

2. The method according to claim 1 , wherein the biological sample is determined to have a high amount of expression of the hTROP2 gene at mRNA level when the log 2 [FPKM+1] value exceeds any one selected from the group consisting of 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.

3. The method according to claim 1 , wherein the biological sample is determined to have a high amount of expression of the hTROP2 gene at mRNA level when the log 2 [FPKM+1] value exceeds any one selected from the group consisting of 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0.

4. The method according to claim 1 , wherein the biological sample is determined to have a high amount of expression of the hTROP2 gene at mRNA level when the log 2 [FPKM+1] value exceeds 7.0.

5. The method according to claim 1 , wherein the biological sample is determined to have a high amount of expression of the SLFN11 gene at mRNA level when the log 2 [FPKM+1] value exceeds any one selected from the group consisting of 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, and 4.0.

6. The method according to claim 1 , wherein the biological sample is determined to have a high amount of expression of the SLFN11 gene at mRNA level when the log 2 [FPKM+1] value exceeds any one selected from the group consisting of 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, and 3.0.

7. The method according to claim 1 , wherein the biological sample is determined to have a high amount of expression of the SLFN11 gene at mRNA level when the log 2 [FPKM+1] value exceeds 3.0.

8. The method according to claim 1 , wherein the biological sample includes a tumor sample.

9. The method according to claim 1 , wherein the anti-hTROP2 antibody-drug conjugate is an antibody-drug conjugate in which a drug-linker is shown by the formula:

wherein A represents a connecting position to the anti-hTROP2 antibody,
and the anti-hTROP2 antibody and linker moiety of the drug-linker are conjugated to each other via a thioether bond.

10. The method according to claim 9 , wherein the anti-hTROP2 antibody is an antibody consisting of a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 2.

11. The method according to claim 9 , wherein the anti-hTROP2 antibody is an antibody consisting of a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 2, and wherein a lysine residue at the carboxyl terminus of the heavy chain of the anti-hTROP2 antibody is deleted.

12. The method according to claim 9 , wherein an average number of units of the drug-linker conjugated per antibody molecule ranges from 2 to 8.

13. The method according to claim 9 , wherein an average number of units of the drug-linker conjugated per antibody molecule ranges from 3.5 to 4.5.

14. The method according to claim 1 , wherein the anti-hTROP2 antibody-drug conjugate is Sacituzumab Govitecan (IMMU-132).

15. The method according to claim 1 , wherein the cancer is a lung cancer, a kidney cancer, a urothelial cancer, a colorectal cancer, a prostate cancer, polymorphic glioblastoma, an ovarian cancer, a pancreatic cancer, a breast cancer, melanoma, a liver cancer, a bladder cancer, a gastric cancer, a cervical cancer, a uterine cancer, a head and neck cancer, an esophageal cancer, a biliary tract cancer, a thyroid cancer, lymphoma, acute myeloid leukemia, acute lymphoid leukemia, or multiple myeloma.

16. A method for identifying a subject to whom a medicament containing an anti-hTROP2 antibody-drug conjugate is to be given, wherein the subject is a human patient suffering from a cancer, the method comprising:
1) obtaining a biological sample from the human patient diagnosed as suffering from a cancer;
2) evaluating an amount of expression of the hTROP2 gene and the SLFN11 gene at mRNA level in the biological sample; and
3) identifying the human patient who provided the biological sample, wherein the biological sample is one that is determined to have a high amount of expression of the hTROP2 gene and the SLFN11 gene, as a subject to whom an anti-hTROP2 antibody-drug conjugate is to be given,
wherein the drug portion of the anti-hTROP2 antibody-drug conjugate comprises a topoisomerase I inhibitor,
wherein a log 2 [FPKM+1] value is measured by RNA sequencing from the biological sample obtained from the human patient diagnosed as suffering from a cancer,
wherein the biological sample is determined to have a high amount of expression of the hTROP2 gene at mRNA level when the log 2 [FPKM+1] value exceeds 6.0, and
wherein the biological sample is determined to have a high amount of expression of the SLFN11 gene at mRNA level when the log 2 [FPKM+1] value exceeds 2.0, and
the subject identified in step 3) is treated with the anti-hTROP2 antibody-drug conjugate.

17. The method according to claim 16 , wherein a log 2 [FPKM+1] value is measured by RNA sequencing from the biological sample obtained from the human patient diagnosed as suffering from a cancer, wherein the biological sample is determined to have a high amount of expression of the hTROP2 gene at mRNA level when the log 2 [FPKM+1] value exceeds any one selected from the group consisting of 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0,
and wherein the biological sample is determined to have a high amount of expression of the SLFN11 gene at mRNA level when the log 2 [FPKM+1] value exceeds any one selected from the group consisting of 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Okajima Daisuke
• Yasuda Satoru
• Enomoto Kei

Classifications

• G01N33/575

  for cancer · CPC title

• G01N2030/8827

  involving nucleic acids · CPC title

• C12Q2600/158

  Expression markers · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title

• C07K16/30

  from tumour cells · CPC title