Treatment of trop-2 expressing triple negative breast cancer with sacituzumab govitecan and a rad51 inhibitor

一种抑制剂、拓扑替康的技术，应用在用沙妥珠单抗格维替康和RAD51抑制剂治疗表达TROP-2的三阴性乳腺癌领域，能够解决延迟、剂量减少等问题

Inactive Publication Date: 2019-10-29
IMMUNOMEDICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, at this dose, there is often a delay within or between cycles and the need for dose reductions

Method used

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  • Treatment of trop-2 expressing triple negative breast cancer with sacituzumab govitecan and a rad51 inhibitor
  • Treatment of trop-2 expressing triple negative breast cancer with sacituzumab govitecan and a rad51 inhibitor
  • Treatment of trop-2 expressing triple negative breast cancer with sacituzumab govitecan and a rad51 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0213] Example 1. Targeted therapy of gastrointestinal cancer with IMMU-132 (sartuzumab gvetecan, an anti-Trop-2-SN-38 antibody drug conjugate (ADC))

[0214] Trop-2 is a very prevalent tumor-associated glycoprotein in many epithelial cancers. Elevated expression has been associated with more aggressive disease and poor prognosis. A humanized mAb that binds the extracellular domain of Trop-2 was conjugated to SN-38 (IMMU-132; average drug:mAb ratio = 7.6), which is the active ingredient of CPT-11. Following potent activity in human tumor xenografts, phase I / II trials were initiated in patients (pts) with different solid tumors, including gastrointestinal cancers.

[0215] method : Patients with metastatic cancer were recruited after failure of standard therapy to start at a dose of 8.0 mg / kg given on days 1 and 8 of a 3-week cycle. The MTD was determined to be 12 mg / kg; dose levels of 8 and 10 mg / kg were selected for Phase II trials.

[0216] result: Sixty patients with...

Embodiment 2

[0219] Example 2. Production and use of anti-Trop-2-SN-38 antibody-drug conjugates

[0220] Humanized RS7 (hRS7) anti-Trop-2 antibodies were generated as described in US Patent No. 7,238,785, the Figures and Examples section of which are incorporated herein by reference. According to U.S. Patent 7,999,083 (Examples 10 and 12 of which are incorporated herein by reference), SN-38 attached to a CL2A linker was generated and combined with hRS7 (anti-Trop-2), hPAM4 (anti-MUC5ac), hA20 (anti- -CD20) or hMN-14 (anti-CEACAM5) antibody conjugates. The conjugation protocol yielded a ratio of about 6 SN-38 molecules attached per antibody molecule.

[0221] Immunocompromised athymic nude mice (female) bearing subcutaneous human pancreatic or colon tumor xenografts were treated or not with specific CL2A-SN-38 conjugates or control conjugates. The therapeutic efficacy of the specific conjugates was observed. figure 1shows the Capan 1 pancreatic tumor model in which specific CL2A-SN-38 co...

Embodiment 3

[0222] Example 3. Efficacy of anti-Trop-2-SN-38 ADC against different epithelial cancers in vivo

[0223] Summary

[0224] The purpose of this study was to evaluate the efficacy of the SN-38-anti-Trop-2(hRS7) ADC against several human solid tumor types and to assess its tolerability in mice and monkeys, which are similar to humans and have the same Tissue cross-reactivity. Two SN-38 derivatives, CL2-SN-38 and CL2A-SN-38, were conjugated to the anti-Trop-2 humanized antibody hRS7. Stability, binding and cytotoxicity of the immunoconjugates were characterized in vitro. Efficacy was tested in five different human solid tumor-xenograft models expressing the Trop-2 antigen. Toxicity was assessed in mice and cynomolgus monkeys.

[0225] The hRS7 conjugates of the two SN-38 derivatives were highly effective in drug substitution (~6), cell binding (K d ~1.2nmol / L), cytotoxicity (IC 50 ~2.2nmol / L) and in vitro serum stability (t / 1 / 2 ~20 hours) are equivalent. Exposure of cells...

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Abstract

The present invention relates to treatment of Trop-2 postive cancers with the combination of anti-Trop-2 ADC and a Rad51 inhibitor. Preferably the drug conjugated to the antibody is SN-38, and the ADCis sacituzumab govitecan. The ADC may be administered at a dosage of between 4 mg / kg and 16 mg / kg, preferably 4, 6, 8, 9, 10, 12, or 16 mg / kg. When administered at specified dosages and schedules, the combination of ADC and Rad51 inhibitor can reduce solid tumors in size, reduce or eliminate metastases and is effective to treat cancers resistant to standard therapies, such as radiation therapy, chemotherapy or immunotherapy. Surprisingly, the combination is effective to treat cancers that are refractory to or relapsed from irinotecan or topotecan.

Description

[0001] related application [0002] This application claims the benefit under 35 USC § 119(e) of US Provisional Patent Application 62 / 477,216, filed March 27, 2017, the text of which is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been submitted in ASCII format via EFS-Web, and is hereby incorporated by reference in its entirety. Said ASCII copy, created on March 14, 2018, is named IMM372WO1_SL and is 7,916 bytes in size. technical field [0005] The present invention relates to combination therapy for the treatment of Trop-2 expressing cancers with an anti-Trop-2 antibody-drug conjugate (ADC) and a Rad51 inhibitor. The drug conjugated to the anti-Trop-2 antibody can be a drug that induces DNA strand breaks, such as auristatin, colicheamicin, camptothecin (eg, SN-38), or anthracycline class (anthracyclines). Exemplary drugs that induce DNA strand breaks include, but are not limi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/35A61K31/52A61K31/337A61K31/365A61K39/395A61K45/06A61K47/68C07K16/18C07K16/28C07K16/30A61K33/243
CPCA61K47/6849A61K47/6851A61K47/6855A61K47/6857A61K47/6859A61K47/6863C07K16/18C07K2317/24C07K2317/77C07K2317/92A61K47/6803A61P35/04A61K31/4353A61K33/243A61K31/506A61K47/68037A61K2300/00A61K39/39558
Inventor T.M.卡迪罗D.M.戈登堡
Owner IMMUNOMEDICS INC
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