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Combinations of an anti-HER2 antibody-drug conjugate and chemotherapeutic agents, and methods of use

A chemotherapeutic agent, antibody technology, applied in the direction of drug combination, antibody medical components, chemical instruments and methods, etc., can solve problems such as low efficacy

Active Publication Date: 2011-04-27
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The conjugates of maytansinoids linked to the anti-HER2 murine breast cancer antibody TA.1 via the MCC linker are 200 times less potent than the corresponding conjugates with the disulfide linker (Chari et al. (1992) Cancer Res. 127-133)

Method used

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  • Combinations of an anti-HER2 antibody-drug conjugate and chemotherapeutic agents, and methods of use
  • Combinations of an anti-HER2 antibody-drug conjugate and chemotherapeutic agents, and methods of use
  • Combinations of an anti-HER2 antibody-drug conjugate and chemotherapeutic agents, and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0275] Example 1 : Preparation of trastuzumab-MCC-DM1

[0276] since Trastuzumab was purified by buffer exchange at 20 mg / mL in 50 mM potassium phosphate / 50 mM sodium chloride / 2 mM EDTA, pH 6.5, with 7.5 to 10 molar equivalents of succinimidyl 4-(N-maleimide Methyl)cyclohexane-1-carboxylate (SMCC, Pierce Biotechnology, Inc), 20 mM in DMSO or DMA (dimethylacetamide), 6.7 mg / mL (US 2005 / 0169933; US 2005 / 0276812) treated . After stirring at ambient temperature under argon for 2-4 hours, the reaction mixture was filtered through a Sephadex G25 column equilibrated with 50 mM potassium phosphate / 50 mM sodium chloride / 2 mM EDTA, pH 6.5. Alternatively, the reaction mixture was gel filtered with pH 6 of 30 mM citrate and 150 mM sodium chloride. Fractions containing antibody were pooled and assayed. The recovery of trastuzumab-SMCC was 88%.

[0277] The drug-linker intermediate trastuzumab-MCC from above was diluted to a final concentration of 10 mg / ml with 50 mM potassium phosph...

Embodiment 2

[0281] Example 2 : In Vitro Cell Proliferation Assay

[0282] The efficacy of the combinations of the invention was measured by a cell proliferation assay using the following protocol (Promega Corp. Technical Bulletin TB288; Mendoza et al. (2002) Cancer Res. 62:5485-5488). Cell-Titer Glo assay reagents and protocols are commercially available (Promega). The assay assesses the ability of a compound to enter cells and affect cell proliferation. The assay principle is to determine the number of viable cells present by quantifying cellular ATP. Cell-Titer Glo refers to the reagent used for this quantification. It is a homogeneous assay in which addition of Cell-Titer Glo results in cell lysis and generation of a luminescent signal via a luciferase reaction. The luminescent signal is proportional to the amount of ATP present.

[0283] DMSO and media plates: 96-well conical bottom polypropylene plates (Nunc, catalog # 249946)

[0284] Cell plate: 384-well black with lid, tran...

Embodiment 3

[0303] Example 3 : Tumor xenografts in vitro

[0304] Animals suitable for transgenic experiments are available from standard commercial sources. Groups of female CB-17SCID beige mice (Charles River Laboratory) were implanted with 3 million KPL-4 (Her2-overexpressing) breast cancer cells in the mammary fat pad with Matrigel. Groups of female athymic nude mice (Charles RiverLaboratory or Harlan) were implanted with 2x 2mm of MMTV-Her2Fo5 transgenic mammary tumors in the mammary fat pad 3debris. Mouse xenografts were dosed with drug, drug combination, or vehicle on day 0 according to the schedule specified for each tumor model. 5-FU, gemcitabine, carboplatin, and B20-4.1 administered intraperitoneally, pertuzumab administered intravenously or intraperitoneally as indicated, trastuzumab-MCC-DM1 and docetaxel administered intravenously, lapatinib, GDC-0941, and ABT-869 passed Oral administration by gavage. Tumor dimensions were recorded twice weekly during the study. Mouse ...

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Abstract

Combinations of the antibody-drug conjugate trastuzumab-MCC-DM1 and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting tumor cell growth, and for treating disorders such as cancer mediated by HER2 and KDR (VEGFR receptor 1). Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

Description

[0001] Cross References to Related Applications [0002] This non-provisional application filed pursuant to 37 CFR §1.53(b) claims the benefit of US Provisional Application Serial No. 61 / 037,410 filed March 18, 2008 (incorporated herein in its entirety by reference) pursuant to 35 USC §119(e). field of invention [0003] The present invention generally relates to pharmaceutical combinations of compounds having activity against hyperproliferative disorders such as cancer. The present invention also relates to methods of in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or related pathological conditions, using said compound combinations. Background of the invention [0004] HER2 (ErbB2) receptor tyrosine is a member of the epidermal growth factor receptor (EGFR) transmembrane receptor family. Overexpression of HER2 is observed in approximately 20% of human breast cancers and has been implicated in the invasive growth and poor clinical outcome associat...

Claims

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Application Information

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IPC IPC(8): A61K31/337A61K31/416A61K31/513A61K31/517A61K31/5355A61K31/555A61K39/395A61K45/06A61P35/00
CPCA61K31/517A61K47/48584A61K47/48384A61K45/06A61K31/513G01N2500/10G01N33/5011A61K39/39558A61K31/337G01N33/57415A61K31/5355A61K31/555A61K31/416A61K31/5377G01N2800/52A61K47/6855A61P35/00A61P35/02A61P35/04A61P43/00A61K47/68033A61K2300/00A61K31/5365A61K2039/507A61K9/0019G01N33/5044G01N2333/71C07K16/32A61K47/38A61K39/395A61K39/00A61K47/6803
Inventor 利安娜·贝里盖尔·L·菲利普斯马克·X·斯利夫科斯基
Owner GENENTECH INC
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