Combination of antibody-drug conjugate and tubulin inhibitor
Inventors
OGITANI, Yusuke • Ishii, Chiaki • Kamai, Yasuki • SUGIHARA, Kiyoshi • NAGASE, SHOTARO
Assignees
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Publication Number
US-12497465-B2
Publication Date
2025-12-16
Expiration Date
Abstract
A pharmaceutical composition, wherein an antibody-drug conjugate in which a drug-linker represented by the following formula (wherein A represents a connecting position to an antibody) is conjugated to the antibody via a thioether bond, and a tubulin inhibitor are administered in combination, and a method of treatment, wherein the antibody-drug conjugate and the tubulin inhibitor are administered in combination to a subject.
Core Innovation
The invention relates to antibody-drug conjugates (ADCs) in which a drug-linker is conjugated to an antibody via a thioether bond. The drug-linker is represented with A as a connecting position to the antibody, and the average number of drug-linker units per antibody molecule is represented by n. The ADC framework emphasizes linker behavior in cancer cells to release an active payload as a topoisomerase I inhibitory compound, including exatecan as a topoisomerase I inhibitor payload derived from a camptothecin derivative.
The disclosed invention relates to treating cancer by administering a first antibody-drug conjugate and administering a tubulin inhibitor. The first antibody-drug conjugate includes a drug-linker represented by a formula conjugated to an antibody via a thioether bond, where A represents a connecting position to the antibody. The tubulin inhibitor is selected from paclitaxel, docetaxel, cabazitaxel, or eribulin, or a pharmacologically acceptable salt thereof, or nab-paclitaxel, or a second antibody-drug conjugate in which eribulin is conjugated to an antibody via a linker.
The disclosure further specifies antibody characteristics, including that the antibody can be human, mouse, chimeric, or humanized, and that the antibody includes target-binding and internalization requirements. Preferred antibody targets are enumerated as HER2, HER3, TROP2, B7-H3, GPR20, and CDH6, and preferred antibody sequence definitions are provided using CDR/CDRL regions and SEQ ID NOs. The disclosure provides a rationale for combined antitumor activity, cell cycle arrest at S/G2 and/or M phases, apoptosis, and bystander effects arising from topoisomerase I inhibition together with tubulin inhibition.
Claims Coverage
The independent claim set covers cancer treatment by administering a thioether-bonded ADC and a tubulin inhibitor, with five inventive features in the combined claim coverage.
Cancer treatment by administering thioether-bond ADC plus tubulin inhibitor
A method of treating cancer by administering a first antibody-drug conjugate and administering a tubulin inhibitor to a subject, where the first antibody-drug conjugate has a drug-linker conjugated to an antibody via a thioether bond and A represents a connecting position to the antibody.
Defined tubulin inhibitor options including taxanes or eribulin or nab-paclitaxel or second ADC with eribulin
The tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or eribulin, or a pharmacologically acceptable salt thereof, or nab-paclitaxel, or a second antibody-drug conjugate in which eribulin is conjugated to an antibody via a linker.
Antibody target selection by dependent claim
Dependent claim coverage specifies a first antibody-drug conjugate using an anti-TROP2 antibody, and in further dependents defines the anti-TROP2 antibody by heavy- and light-chain amino-acid sequence ranges taken from SEQ ID NO: 5 and SEQ ID NO: 6.
Drug-linker loading quantification range
Dependent claim coverage specifies that the method uses an average number of drug-linker units conjugated per antibody molecule between 3.5 and 4.5.
Administration as separate formulations with selectable timing
Dependent claim coverage specifies separate formulations administered simultaneously or at different times.
The inventive coverage centers on combining a thioether-bonded ADC, with A as the antibody connecting position, with specified tubulin inhibitors including taxanes, eribulin, nab-paclitaxel, or a second ADC delivering eribulin via a linker. Dependent claims refine antibody target definition, average drug-linker loading, and administration/formulation timing.
Stated Advantages
Antitumor activity.
Cell cycle arrest at S/G2 and/or M phases.
Apoptosis.
Bystander effects.
Documented Applications
Treating cancer.
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