Method for producing antibody-drug conjugate
Inventors
Yamaguchi, Tatsuya • KOUKO, TAKASHI • Noguchi, Shigeru • Yamane, Yohei • KONDO, FUMIKATSU • Aoki, Takahiro • Takeda, Tadahiro • SAKANISHI, KOHEI • Sato, Hitoshi • Ueda, Tsuyoshi • Matuura, Shinji • Kurahashi, Kei • Kitagawa, Yutaka • Nakamura, Tatsuya
Assignees
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Publication Number
US-12503489-B2
Publication Date
2025-12-23
Expiration Date
Abstract
Crystals of the compound represented by formula (1), a method for the production thereof, and a method for producing an antibody-drug conjugate using the crystals.
Core Innovation
The invention relates to a method for producing an antibody-drug conjugate in which a drug-linker represented by formula (19) is conjugated to an antibody via a thioether bond. The method includes reducing an antibody and then reacting the reduced antibody with a solution obtained by dissolving crystals of a compound represented by formula (1). The connecting position to the antibody is represented by A in formula (19).
The crystals of the compound represented by formula (1) are produced by preparing a solution in which the compound represented by formula (1) is dissolved using a lower ketone and a lower alcohol as solvents, wherein the lower ketone is acetone and the lower alcohol is 1-propanol or 2-butanol, and then precipitating crystals of the compound represented by formula (1) from the solution. The crystals show main peaks at diffraction angles (2θ) of 5.6±0.2°, 5.8±0.2°, 15.5±0.2°, 17.9±0.2°, 20.5±0.2°, 21.4±0.2°, and 22.0±0.2° in powder X-ray diffraction obtained by irradiation with copper Kα radiation.
The disclosed conjugation framework further specifies antibodies including anti-HER2, anti-HER3, anti-TROP2, anti-B7-H3, or anti-GPR20 antibodies. The document also relates the antibody-drug conjugate to internalization into cancer cells and to producing an antitumor topoisomerase I inhibitory species with a bystander effect.
Claims Coverage
The consolidated claim coverage centers on producing an antibody-drug conjugate by thioether-bond conjugation of a drug-linker represented by formula (19) to an antibody using reduced antibody and a solution of dissolved crystals of formula (1). The claims also define the crystals of formula (1) by an acetone and 1-propanol or 2-butanol crystallization route and by specified powder X-ray diffraction main peak positions, and one independent claim restricts the antibody to specified target antibodies.
Thioether conjugation using reduced antibody and dissolved crystals of formula (1)
A method for producing an antibody-drug conjugate in which a drug-linker represented by formula (19) is conjugated to an antibody via a thioether bond by reducing an antibody and then adding a solution in which crystals of the compound represented by formula (1) are dissolved to react the solution with the reduced antibody.
Crystals of formula (1) formed by acetone and 1-propanol or 2-butanol
Crystals of the compound represented by formula (1) are produced by preparing a solution in which the compound represented by formula (1) is dissolved, wherein the solution comprises acetone and 1-propanol or 2-butanol as solvents, and then precipitating crystals of the compound represented by formula (1) from the solution.
Powder X-ray diffraction-defined crystalline form of formula (1)
The crystals of the compound represented by formula (1) show main peaks at diffraction angles (2θ) of 5.6±0.2°, 5.8±0.2°, 15.5±0.2°, 17.9±0.2°, 20.5±0.2°, 21.4±0.2°, and 22.0±0.2° in powder X-ray diffraction obtained by irradiation with copper Kα radiation.
Antibody selection restricted to specified targets
The antibody is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, or an anti-GPR20 antibody.
Overall, the claims require production of an antibody-drug conjugate by thioether-bond conjugation of a formula (19) drug-linker to a reduced antibody using dissolved crystals of a defined compound (formula (1)), with the crystals constrained by a specific crystallization route and powder X-ray diffraction fingerprint, and in one claim the antibody is limited to anti-HER2, anti-HER3, anti-TROP2, anti-B7-H3, or anti-GPR20.
Stated Advantages
Industrially improved production method without chromatography.
Internalization into cancer cells produces an antitumor topoisomerase I inhibitory species with a bystander effect.
Documented Applications
Production of an antibody-drug conjugate (ADC) in which a drug-linker represented by formula (19) is conjugated to an antibody via a thioether bond using dissolved crystals of the compound represented by formula (1).
ADC production embodiments that use crystals and specific crystallized adduct forms characterized by powder X-ray diffraction peak constraints.
ADC production method embodiments using specified antibodies, including anti-HER2, anti-HER3, anti-TROP2, anti-B7-H3, or anti-GPR20 antibodies.
Antibody-drug conjugate directed to cancer cells.
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