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US-12616750-B2 - Combination therapy utilizing DNA alkylating agents and ATR inhibitors

US12616750B2US 12616750 B2US12616750 B2US 12616750B2US-12616750-B2

Abstract

The present invention relates to synergistic combinations of DNA-alkylating ADCs and ATR inhibitors.

Inventors

  • Carl Deutsch
  • Birgit Piater
  • Nicolas RASCHE
  • Heike DAHMEN
  • Frank Zenke
  • Astrid Zimmermann
  • Marcel RIEKER

Assignees

  • MERCK PATENT GMBH

Dates

Publication Date
20260505
Application Date
20191014
Priority Date
20181015

Claims (12)

  1. 1 . A method for treating a HER2 expressing cancer in a subject in need thereof, comprising administering to the subject in any order an Ataxia telangiectasia and Rad3-related (ATR) inhibitor and a duocarmycin bearing antibody-drug conjugate (ADC), wherein the ADC comprises a heavy chain comprising the amino acid sequence according to SEQ ID NO: 17 and a light chain comprising the amino acid sequence according to SEQ ID NO: 18.
  2. 2 . The method according to claim 1 , wherein the ATR inhibitor is selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, or a pharmaceutically acceptable salt thereof, wherein compounds 1-8 are defined as follows:
  3. 3 . The method according to claim 2 , wherein the ATR inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof.
  4. 4 . The method according to claim 1 , wherein the subject underwent at least one round of prior cancer therapy; wherein, optionally, the cancer was resistant or became resistant to prior therapy.
  5. 5 . The method according to claim 1 , further comprising administering a chemotherapy (CT), radiotherapy (RT), or chemotherapy and radiotherapy (CRT) to the subject.
  6. 6 . The method according to claim 5 , wherein the ATR inhibitor and the duocarmycin bearing ADC are administered during the lead phase, whereas during the maintenance phase the ATR inhibitor but not the duocarmycin bearing ADC are administered.
  7. 7 . The method according to claim 6 , wherein the ATR inhibitor and the duocarmycin bearing ADC are administered during the lead phase, whereas A during the maintenance phase the duocarmycin bearing but not the ATR inhibitor are administered.
  8. 8 . The method according to claim 1 , wherein the duocarmycin bearing ADC is selected from the group consisting of DUBA, DDM and DSA.
  9. 9 . The method according to claim 1 , wherein the heavy chain comprises a C-terminal sortase-A motif LPETGS of SEQ ID NO: 31.
  10. 10 . The method according to claim 1 , wherein the heavy chain additionally comprises a (G4S)3-spacer and a sortase-A motif LPETGS of SEQ ID NO: 30.
  11. 11 . The method according to claim 1 , wherein the cancer is selected from the group consisting of small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), colorectal cancer (CRC), primary neuroendocrine tumors and sarcoma or PARPi-resistant recurrent cancer.
  12. 12 . The method according to claim 2 , wherein the ATR inhibitor is Compound 3 or a pharmaceutically acceptable salt thereof, or Compound 4 or a pharmaceutically acceptable salt thereof, or Compound 5 or a pharmaceutically acceptable salt thereof, wherein compounds 3-5 are defined as follows:

Description

SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 6, 2025, is named MERCK-5017_SL.txt and is 44,414 bytes in size. FIELD OF THE INVENTION The present invention relates to a combination therapy utilizing ATR inhibitors and a DNA alkylating agent attached to an antibody molecule, thus forming an antibody drug conjugate, for the treatment of cancer. BACKGROUND OF THE INVENTION While the global cancer burden is still high with 10-20 million people being diagnosed with cancer and up to 10 million cancer-related deaths yearly, academia and industry are seeking to develop more and more sophisticated therapies to combat cancer. Duocarmyins are a class of highly potent antitumour drug candidates. Synthetic analogs of duocarmycins include adozelesin, bizelesin, and carzelesin. As members of the cyclopropylpyrroloindole family, these investigational drugs have progressed into clinical trials for the treatment of cancer. The first member of the duocarmycin family to be evaluated in vivo was CC-1065, and despite showing moderate antitumor activity, hepatic toxicity limited its effectiveness. At this point in time, clinical development is not reported for any member of the duocarmycin family. In efforts to improve the therapeutic index of duocarmycin-based therapeutics, several ADCs have been developed including BMS-936561 (anti-CD70) and SYD985 (anti-HER2). BMS-936561 was first analyzed in patients with advanced clear cell carcinoma and B-cell non-Hodgkin lymphoma; however, the clinical trial was stopped during Phase I despite being tolerated at doses up to 8 mpk. More recently, Synthon generated SYD985 (trastuzumab duocarmycin), which utilizes a duocarmycin prodrug known as seco-DUBA conjugated with a cleavable linker to trastuzumab, as an alternative to ado-trastuzumab emtansine. SYD985 is currently in phase III clinical study. Despite of several attempts no drug based on a member of the duocarmycin family has been approved for human therapy yet, neither based on a duocarmycin as such nor as an duocarmycin bearing ADC. There is still a highly unmet need in the art for improved cancer therapies, both in terms of effectiveness as well as safety. Establishment of combination therapy for ADCs might pose a strategy for increasing efficacy, diminish side-effects and slow down resistance development especially because single agent therapy has seldom been curative. SUMMARY OF THE INVENTION Several ATRis (Ataxia Telangiectasia and RAD3-related protein inhibitors), which inhibit DNA damage repair, are currently in clinical development. None of this has been approved yet. During the research work that lead to the present invention, the inventors surprisingly found that the combination of a duocarmycin bearing ADC with an ATR inhibitor does not only show a combined efficacy, but a highly synergistic effect. It was hypothesized by the present inventors that a combination of DNA-damage response inhibitors (DDRis) might pose an additional strategy to an improved cancer therapy based on a duocarmycin bearing ADC. Several different DDRi were selected and tested in in vitro and in vivo models. HCC-1954 and MDA-MB-468 cancer cells were treated with a combination of the selected DDRis and duocarmycin alone or attached to an antibody, and the antiproliferative effects of the combination treatment were compared to the effects of the single agents alone. “Naked” duocarmycins as well as duocarmycin bearing ADCs were combined with several DDRi known in the art. The mode of actions of such DDRis were manyfold, e.g. decreasing Rad 51 expression, CHK1 inhibition, WEE1 kinase inhibition, O6-alkylguanine-DNA alkyltransferase inhibition, DN-PK inhibition Parp inhibition MTH1 inhibition, ATR inhibition, CHK1 inhibition, NEK1 inhibition, TOP2 inhibition, Her2 inhibition and others. The experiments leading to the present invention surprisingly showed that exclusively inhibitors of the kinase ATR and inhibitors to its major downstream effector checkpoint kinase 1 (CHK1), which play a central role in the response to replication stress, enhanced the cytotoxic effects of the duocarmycin bearing ADC in a highly synergistic manner. Several duocarmycin based ADCs showed strong synergistic effects in combination with different ATR inhibitors in vitro as well as in vivo. rag2 mice bearing a HER2-expressing NCI-N87 tumor were treated with HER2-targeting duocarmycin-ADC and two different ATR inhibitors. The ATR inhibitors monotreatment showed very mild tumor growth inhibition while the treatment with the ADC at concentrations below the maximum effective dose led to a partial tumor response. The combination treatment, however, resulted in very strong anti-tumor effects while being well tolerated. The present study demonstrates the superiority of combining the targeted delivery of duocarmycin to the tu