Duocarmycin ADCs showing improved in vivo antitumor activity
Inventors
DOKTER, Willem • GOEDINGS, Peter Johannes • Verheijden, Gijsbertus Franciscus Maria • Beusker, Patrick Henry
Assignees
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Publication Number
US-11382982-B2
Publication Date
2022-07-12
Expiration Date
Abstract
The present invention relates to duocarmycin-containing antibody-drug conjugates (ADCs) for use in the treatment of human solid tumours and haematological malignancies expressing HER2, in particular breast cancer, gastric cancer, bladder cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer or osteosarcoma, and acute lymphoblastic leukaemia. In particular, the present invention relates to duocarmycin-containing ADCs for use in the treatment of human solid tumours with HER2 IHC 2+ or 1+ and HER2 FISH negative tissue status. Advantageously, the present invention relates to duocarmycin-containing ADCs for use in the treatment of triple negative breast cancer (TNBC).
Core Innovation
The invention relates to duocarmycin-containing antibody-drug conjugates (ADCs) in which an anti-HER2 antibody or antibody fragment able to bind HER2 is linked to a duocarmycin drug through a defined linker-drug conjugate structure. The compounds are defined by formula (I) and include parameters n (0, 1, 2, or 3) and an average DAR (m) from 1 to 4, with R1 and R2 substituent selections from defined groups.
The described compounds include duocarmycin-containing HER2-targeting ADCs, including examples such as SYD985 and SYD983, and the patient population is defined by HER2-positive bladder cancer. The partial content further indicates HER2 expression or status conditions, including HER2 IHC 2+/1+ and HER2 FISH-negative status, with emphasis on solid tumors and hematological malignancies, including triple-negative breast cancer (TNBC).
The invention is presented as solving the need for improved antitumor activity using duocarmycin ADCs, including unexpected improved in vivo antitumor activity of the duocarmycin ADCs versus trastuzumab and T-DM1. The partial content states that the improved activity is particularly noted in low-grade HER2 models and describes evaluation using representative PDX xenograft model testing and intended clinical evaluation, including a first-in-human phase I study (NCT02277717).
Claims Coverage
The partial claim set includes one independent claim. The independent claim covers a method of treating HER2-positive bladder cancer by administering a therapeutically effective amount of a defined duocarmycin-containing compound of formula (I), with the main inventive features centered on the anti-HER2 antibody/fragment binding HER2 and the specified ADC parameter constraints (n and average DAR m) together with defined R1 and R2 selections.
Treating HER2-positive bladder cancer with formula (I) duocarmycin ADCs
A method of treating bladder cancer in a human patient by administering a therapeutically effective amount of a compound of formula (I), wherein anti-HER2 Ab is an anti-HER2 antibody or antibody fragment able to bind HER2; n is 0, 1, 2, or 3; m represents an average DAR of from 1 to 4; and R1 and R2 are selected from the group(s) defined for those variables; wherein the patient has HER2 positive bladder cancer.
Across the independent claim, the coverage is defined by a duocarmycin-containing formula (I) ADC for treating HER2-positive bladder cancer, with binding to HER2 by the anti-HER2 antibody/fragment and with n and average DAR m constrained to the stated ranges, and with R1 and R2 restricted to the defined groups. The dependent claims further refine the antibody choice, ADC form including formula (II), HER2 selection criteria, narrower DAR ranges, and combinations with specified therapeutic or chemotherapeutic agents.
Stated Advantages
Unexpected improved in vivo antitumor activity of duocarmycin ADCs versus trastuzumab and T-DM1.
Improved antitumor activity particularly in low-grade HER2 models.
Documented Applications
Treating bladder cancer in a human patient with HER2 positive bladder cancer using a therapeutically effective amount of a compound of formula (I).
Using the approach for HER2-targeting duocarmycin ADC treatment context in solid tumors and hematological malignancies, including triple-negative breast cancer (TNBC) as described in the partial content.
Evaluation in representative PDX xenograft model testing as described in the partial content.
First-in-human phase I clinical evaluation context referenced as NCT02277717 as described in the partial content.
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