Methods of treating her2 positive cancer with her2 receptor antagonist in combination with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin

A technology of receptor antagonist and camptothecin, which is applied in the field of treating HER2-positive cancers in mammals, can solve problems such as the danger of chemotherapy, and achieve the effects of improving therapeutic effect, enhancing side effects, and inhibiting tumor growth and/or proliferation

Inactive Publication Date: 2012-05-30
ENZON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It has also been reported that treatment with trastuzumab alone or in combination with chemotherapy resulted in heart failure
It has also been reported that patients receiving trastuzumab in combination with anthracycline-based chemotherapy are at risk

Method used

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  • Methods of treating her2 positive cancer with her2 receptor antagonist in combination with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin
  • Methods of treating her2 positive cancer with her2 receptor antagonist in combination with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin
  • Methods of treating her2 positive cancer with her2 receptor antagonist in combination with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin

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Experimental program
Comparison scheme
Effect test

Embodiment approach

[0297] Alternative embodiments for the treatments described herein include:

[0298]

[0299] wherein (n) is an integer from about 28 to 341 such that the total molecular weight of the polymeric portion of the compound of formula (II) is from about 5,000 to about 60,000 Daltons, preferably about 20,000 or 40,000 Daltons.

[0300] In other embodiments, the treatments described herein utilize the polymeric compounds described in WO2005 / 028539, the contents of which are incorporated herein by reference in their entirety.

[0301] C. HER2 antagonists

[0302] Many types of cancer are associated with elevated ER2 protein and gene levels. HER2 proteins catalyze the transfer of terminal phosphates from ATP to tyrosine residues of protein substrates. HER2 receptor antagonists and HER2 antagonists generally refer to compounds that inhibit the function or expression of the HER2 protein or gene. HER2 receptor antagonists can inhibit HER2 receptor function directly or through downst...

Embodiment 1

[0382] Example 1. Toxicity Data

[0383] The maximum tolerated dose ("MTD") of 4Arm-PEG-Gly-(7-ethyl-10-hydroxycamptothecin) (compound 9) was studied using nude mice. Mice were monitored for 14 days for mortality and signs of disease and sacrificed when body weight loss > > 20% of pre-treatment body weight.

[0384] Table 2 below shows the maximum tolerated dose for each compound (single and multiple dose administration). Mice were administered each dose of the multi-dose administration on alternate days for 10 days and then observed for an additional 4 days, thus a total of 14 days.

[0385] Table 2. MTD data in nude mice

[0386]

[0387] The MTD of 4Arm-PEG-Gly-(7-ethyl-10-hydroxycamptothecin) (compound 9) was found to be 30 mg / kg when administered as a single dose and 10 mg when administered in multiple doses (q2d x 5) / kg.

Embodiment 2

[0388] Example 2. Properties of PEG conjugates

[0389] Table 3 below shows the solubility of 4 different PEG-(7-ethyl-10-hydroxycamptothecin) conjugates in saline solution. All four PEG-(7-ethyl-10-hydroxycamptothecin) conjugates showed good solubility up to 4 mg / mL equivalent to 7-ethyl-10-hydroxycamptothecin. In human plasma, 7-ethyl-10-hydroxycamptothecin was released stably from the PEG conjugate with a doubling time of 22 to 52 minutes, and the release exhibited pH and concentration as described in Example 3 below. rely.

[0390] Table 3. Properties of PEG-7-ethyl-10-hydroxycamptothecin conjugates

[0391]

[0392] a 7-Ethyl-10-hydroxycamptothecin is insoluble in saline

[0393] b PEG conjugate half-life

[0394] c Rate of formation of 7-ethyl-10-hydroxycamptothecin from conjugates

[0395] The PEG-Gly-7-ethyl-10-hydroxycamptothecin conjugate exhibits good stability in saline and other aqueous media for up to 24 hours at room temperature.

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Abstract

The present invention relates to methods of treating a HER2 positive cancer in mammals. The present invention includes administering a HER2 antagonist in combination with a polymeric prodrug of 7-ethyl-10-hydroxycamptothecin to the mammals in need thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application 61 / 227,599, filed July 22, 2009, the contents of which are incorporated herein by reference. field of invention [0003] The present invention relates to methods of treating HER2 positive cancers. In particular, the present invention relates to methods of treating HER2-positive cancers in mammals by administering (administering) a HER2 antagonist in combination with a polyethylene glycol conjugate of 7-ethyl-10-hydroxycamptothecin. Background of the invention [0004] Breast cancer is the most common type of cancer among American women. Recent studies have shown that about 20-25% of breast cancers are HER2 (human epidermal growth factor receptor) positive. The HER2 protein, also known as the HER2 receptor or HER2 / neu or ErbB2, is found on the surface of some normal cells in the body. HER2 functions to regulate cell growth and survival. HER2 prote...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K31/44
CPCA61K39/395C07K16/32A61K2039/505A61K31/44C07K2316/96C07K2317/24A61P35/00A61P35/04A61P43/00C07K2317/73A61K2300/00
Inventor 普加·萨普拉
Owner ENZON PHARM INC
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