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EP-4737483-A1 - ANTIBODY-DRUG CONJUGATE PRODUCTION METHOD INCLUDING PURIFICATION STEP USING ACTIVATED CARBON MATERIAL

EP4737483A1EP 4737483 A1EP4737483 A1EP 4737483A1EP-4737483-A1

Abstract

Provided is a method for producing an antibody-drug conjugate that includes a purification process for efficiently removing by-product(s) derived from an exatecan compound. Provided is a method for producing an antibody-drug conjugate, in which a drug-linker represented by the following formula, wherein A represents the connecting position to an antibody, and the antibody are conjugated via a thioether bond, the method including the step of: (i) removing, from a solution containing the antibody-drug conjugate, byproduct(s) derived from an exatecan compound contained in the solution by using an activated carbon material.

Inventors

  • FUKUBA Atsuki
  • HONZUMI MASATOSHI
  • SHIRAISHI SHOHEI
  • IIDA KOUKI

Assignees

  • Daiichi Sankyo Company, Limited

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. A method for producing an antibody-drug conjugate, in which a drug-linker represented by formula (1): wherein A represents the connecting position to an antibody; and the antibody are conjugated via a thioether bond, the method comprising the step of: (i) removing, from a solution containing the antibody-drug conjugate, by-product(s) derived from an exatecan compound contained in the solution by using an activated carbon material.
  2. The production method according to claim 1, wherein the step (i) is a step of filtering the solution containing the antibody-drug conjugate through an activated carbon filter.
  3. The production method according to claim 1 or 2, wherein the step (i) is a step of filtering the solution containing the antibody-drug conjugate through an activated carbon filter, wherein the solution is passed through the activated carbon filter only once.
  4. The production method according to claim 2 or 3, wherein the method comprises a step of washing the activated carbon filter before use, prior to the step (i).
  5. The production method according to claim 4, wherein an aqueous solution containing a surfactant is used in the washing step before use.
  6. The production method according to claim 4 or 5, wherein an aqueous solution of polysorbate 20 or an aqueous solution of polysorbate 80 is used in the washing step before use.
  7. The production method according to claim 4 or 5, wherein an aqueous solution of polysorbate 20 is used in the washing step before use.
  8. The production method according to claim 4 or 5, wherein an aqueous solution of polysorbate 80 is used in the washing step before use.
  9. The production method according to any one of claims 1 to 8, wherein the activated carbon contained in the activated carbon material has a specific surface area of 10 to 10000 m 2 /g.
  10. The production method according to any one of claims 1 to 9, wherein the activated carbon contained in the activated carbon material has an average particle size of 2 µm or more.
  11. The production method according to any one of claims 1 to 10, wherein at least 90% by weight of the activated carbon contained in the activated carbon material has an average particle size of 5 to 40 µm.
  12. The production method according to any one of claims 1 to 11, wherein the temperature of the solution containing the antibody-drug conjugate used in the step (i) is 0°C to 30°C.
  13. The production method according to any one of claims 1 to 12, wherein the temperature of the solution containing the antibody-drug conjugate used in the step (i) is 10°C to 20°C.
  14. The production method according to any one of claims 1 to 13, wherein the temperature of the solution containing the antibody-drug conjugate used in the step (i) is about 15°C.
  15. The production method according to any one of claims 1 to 14, wherein the pH of the solution containing the antibody-drug conjugate used in the step (i) is 4.0 to 6.0.
  16. The production method according to any one of claims 1 to 15, wherein the pH of the solution containing the antibody-drug conjugate used in the step (i) is about 5.
  17. The production method according to any one of claims 1 to 15, wherein the pH of the solution containing the antibody-drug conjugate used in the step (i) is about 4.5.
  18. The production method according to any one of claims 1 to 17, wherein the method comprises the steps of: (ii) reducing an antibody with a reducing agent; (iii) reacting the compound represented by formula (2): with the antibody reduced in the step (ii); (iv) adding a reagent having a thiol group and reacting the reagent with the compound represented by the formula (2) that remains after the step (iii).
  19. The production method according to any one of claims 1 to 18, wherein the method comprises the step (i) as a step after the step (iv).
  20. The production method according to any one of claims 1 to 19, wherein the by-product(s) derived from an exatecan compound comprise a compound in which the reducing agent used in the step (ii) is added to the maleimidyl group of the compound represented by the formula (2) and/or a compound in which the reagent having a thiol group used in the step (iv) is added to the maleimidyl group of the compound represented by the formula (2).

Description

Technical Field The present invention relates to a method for producing an antibody-drug conjugate, comprising a purification step using an activated carbon material. In particular, the present invention relates to a method for producing an antibody-drug conjugate, comprising a purification step in which an activated carbon material is used to remove by-product(s) derived from an exatecan compound. Background art An antibody-drug conjugate (ADC) having a drug with cytotoxicity conjugated to an antibody capable of binding to an antigen expressed on the surface of cancer cells and cellular internalization, can deliver the drug selectively to cancer cells and thus be expected to cause accumulation of the drug within cancer cells and to kill the cancer cells (Non-Patent References 1 to 5). As one such antibody-drug conjugate, an antibody-drug conjugate comprising an antibody and a derivative of exatecan, which is a topoisomerase I inhibitor, as its components (hereinafter also referred to as "DXd-ADC") is known (Patent References 1 to 6 and Non-Patent References 6 to 9). These antibody-drug conjugates have superior antitumor effects and safety and, for example, Trastuzumab deruxtecan has already been approved as a medicament worldwide, with many other clinical studies currently underway. Generally, an antibody-drug conjugate comprises a drug with a high cytotoxic activity that is conjugated to an antibody. It is preferable to remove, as far as possible, highly active impurities derived from the drug that is not conjugated to the antibody, from the active pharmaceutical ingredient of the antibody-drug conjugate. This is an extremely important requirement for the quality of the active pharmaceutical ingredient. Examples in Patent References 7 to 15 describe methods for producing an antibody-drug conjugate other than DXd-ADC. These production methods comprise a step of chromatography-mediated purification such as hydrophobic chromatography or gel filtration chromatography. Patent References 1 to 6 describe methods for producing DXd-ADC, which is an antibody-drug conjugate, in which an antibody is conjugated with a drug-linker intermediate and the resulting crude antibody-drug conjugate is purified. Examples in Patent References 2 to 4 describe the purification of the above-described crude antibody-drug conjugate by ultrafiltration using a sorbitol-containing acetate buffer. Patent Reference 5 describes that the crude antibody-drug conjugate can be purified by ultrafiltration using an acetate buffer, a histidine buffer, or a phosphate buffer. Furthermore, Patent Reference 6 describes that the crude antibody-drug conjugate can be effectively purified by ultrafiltration using a salt-containing buffer. Examples in Patent Reference 16 describe a method for removing pyrrolobenzodiazepine-related impurities from a mixture resulting from the generation of a conjugate of pyrrolobenzodiazepine and an antibody (hereinafter also referred to as "PBD-ADC") through activated carbon filtration. As described above, several technologies are known that are related to methods of purifying antibody-drug conjugates. Nevertheless, in the case of DXd-ADCs, there has been a demand for the development of an improved method for purifying highly active impurities derived from drugs. Citation List Patent References Patent Reference 1: International Publication No. WO 2014/057687Patent Reference 2: International Publication No. WO 2015/098099Patent Reference 3: International Publication No. WO 2015/115091Patent Reference 4: International Publication No. WO 2015/155998Patent Reference 5: International Publication No. WO 2017/002776Patent Reference 6: International Publication No. WO 2020/022363Patent Reference 7: International Publication No. WO 2002/098883Patent Reference 8: International Publication No. WO 2005/037992Patent Reference 9: International Publication No. WO 2005/084390Patent Reference 10: International Publication No. WO 2006/086733Patent Reference 11: International Publication No. WO 2007/024536Patent Reference 12: International Publication No. WO 2010/141566Patent Reference 13: International Publication No. WO 2011/039724Patent Reference 14: International Publication No. WO 2012/135517Patent Reference 15: International Publication No. WO 2015/104359Patent Reference 16: International Publication No. WO 2014/143622 Non Patent References Non Patent Reference 1: Ducry L., et al., Bioconjugate Chem. (2010), 21(1), 5-13.Non Patent Reference 2: Alley S. C., et al., Current Opinion in Chemical Biology (2010), 14(4), 529-537. Non Patent Reference 3: Damle N. K., Expert Opin. Ther. (2004), 4 (9), 1445-1452.Non Patent Reference 4: Senter P. D., et al., Nature Biotechnology (2012), 30(7), 631-637.Non Patent Reference 5: Howard A., et al., J. Clin. Oncol. (2011), 29(4), 398-405.Non Patent Reference 6: Ogitani Y., et al., Clinical Cancer Research (2016), 22(20), 5097-5108.Non Patent Reference 7: Ogitani Y., et al., Cancer Science (2016), 107(