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-10603387-B2
Publication Date
2020-03-31
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
Duocarmycin-containing HER2-targeting antibody-drug conjugates (ADCs) are disclosed for treating cancer in a human patient. The disclosed compound is a compound of formula (I) in which the anti-HER2 antibody is trastuzumab, and the ADC includes defined structural parameters including n selected from 0, 1, 2, or 3, and m representing an average DAR of from 1 to 4. The disclosure further includes defined selections for R1, y, and R2.
The disclosed treatment is directed to patients having HER2-expressing tumors meeting specific biomarker conditions. For solid tumors, the solid tumor is HER2 IHC 2+ or 1+ and HER2 FISH negative, and the solid tumor types include gastric cancer, bladder cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer, or osteosarcoma. The disclosure also focuses on breast cancer patients in which HER2 expression is defined as IHC 0, IHC 1+, or IHC 2+/FISH negative.
The disclosure emphasizes that duocarmycin ADCs provide unexpectedly improved in vivo antitumor activity compared with trastuzumab and T-DM1, with particular emphasis on models having the lowest HER2 expression (IHC 1+). The corresponding ADC structures are described as cysteine-linked trastuzumab-based ADC structures with defined linker/drug moieties, and the disclosure situates the ADCs in tumor model context, including PDX xenograft models. SYD985 is stated to have ongoing first-in-human Phase I evaluation (NCT02277717).
Claims Coverage
The partial content identifies two independent claim sets. Each is centered on administering a therapeutically effective amount of a formula (I) duocarmycin-containing anti-HER2 ADC having trastuzumab as the anti-HER2 Ab, together with structural parameter constraints and a defined HER2 biomarker-defined patient population.
Trastuzumab-based compound of formula (I) with defined ADC parameters and moiety selections
A method of treating cancer in a human patient comprising administering a therapeutically effective amount of a compound of formula (I) wherein anti-HER2 Ab is trastuzumab, n is 0, 1, 2, or 3, m represents an average DAR of from 1 to 4, and defined R1, y, and R2 selections are present.
HER2-expressing solid tumors that are HER2 IHC 2+ or 1+ and HER2 FISH negative with specified solid tumor types
A method of treating cancer in a human patient wherein the patient has a solid tumor expressing HER2, the solid tumor is HER2 IHC 2+ or 1+, and the solid tumor is HER2 FISH negative, and wherein the solid tumor is gastric cancer, bladder cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer, or osteosarcoma.
Breast cancer patient selection defined by HER2 IHC levels including IHC 0, IHC 1+, or IHC 2+/FISH negative
A method of treating cancer in a human patient wherein the patient has breast cancer that expresses HER2 at a level of IHC 0, IHC 1+, or IHC 2+/FISH negative.
Overall, the independent claims define a trastuzumab-based duocarmycin ADC compound of formula (I) with constrained n and average DAR (m) and defined R1/R2 selections, and then limit the treated patient population by HER2 expression criteria. One claim further restricts to HER2 IHC 2+ or 1+ solid tumors that are HER2 FISH negative, including a defined list of solid tumor types, while another restricts to breast cancer with defined HER2 IHC/FISH-negative categories.
Stated Advantages
Unexpectedly improved in vivo antitumor activity versus trastuzumab and T-DM1, with emphasis on models having the lowest HER2 expression (IHC 1+).
Documented Applications
Treating cancer in a human patient with HER2-expressing solid tumors that are HER2 IHC 2+ or 1+ and HER2 FISH negative, including gastric cancer, bladder cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer, or osteosarcoma.
Treating cancer in a human patient with breast cancer expressing HER2 at IHC 0, IHC 1+, or IHC 2+/FISH negative.
Tumor model evaluation including PDX xenograft models.
First-in-human Phase I evaluation of SYD985 (NCT02277717).
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