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Combination therapies comprising anti-ERBB 3 agents

A combined therapy and pharmaceutical technology, which is applied in drug combinations, antineoplastic drugs, antibody medical components, etc., can solve problems such as changing bioavailability and affecting safety

Inactive Publication Date: 2014-01-29
MERRIMACK PHARMACEUTICALS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, many drugs are known to alter the bioavailability, or otherwise affect the safety of the other drug, when two drugs are co-administered

Method used

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  • Combination therapies comprising anti-ERBB 3 agents
  • Combination therapies comprising anti-ERBB 3 agents
  • Combination therapies comprising anti-ERBB 3 agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Combination therapy with MM-111 and tamoxifen inhibits tumor growth in vivo.

[0064] To compare the effect of combination therapy with MM-111 and tamoxifen on tumor growth in vivo, estrogen-stimulated mice were prepared in a xenograft model using the methods described above or minor variations thereof. Mice were inoculated with tumor forming BT474-M3 cells and given placebo (vehicle control), MM-111, tamoxifen, or a combination of MM-111 and tamoxifen on day 7 and tumor growth was measured over time . as in figure 1 As shown in , this in vivo BT474-M3 xenograft model showed resistance to tamoxifen treatment, but when the combination of MM-111 and tamoxifen was administered to mice, the combination therapy exhibited significant inhibited tumor growth to a greater extent. For the combination group, statistical significance was observed from day 28 when compared to vehicle control, from day 21 when compared to MM-111, and from day 25 when compared to tamox...

Embodiment 2

[0065] Example 2: MM-111 Positively Comparable to Antiestrogens in Inhibiting Estrogen-Stimulated Spheroid Growth sexual union

[0066] Use multicellular spheroids to mimic tumor growth and microenvironmental conditions in vitro. To further investigate the ability of MM-111 to inhibit cell growth when MM-111 is combined with antiestrogens, spheroids of BT474-M3 were prepared using the method described above or a slight variation thereof and treated with ErbB2-binding therapeutics and / or anti-estrogen therapy. Use of MM-111, tamoxifen, or a combination of MM-111 and tamoxifen ( Figure 2a ); trastuzumab, tamoxifen, or a combination of trastuzumab and tamoxifen ( Figure 2b ); MM-111, fulvestrant, or a combination of MM-111 and fulvestrant ( Figure 2c ); trastuzumab, fulvestrant, or a combination of trastuzumab and fulvestrant ( Figure 2d ); or MM-111, trastuzumab, or a combination of MM-111 and trastuzumab ( Figure 2e ) range of doses to treat spheroids of estroge...

Embodiment 3

[0067] Example 3: Positivity of MM-111 to Antiestrogens in Inhibiting Heregulin-Stimulated Spheroid Growth sexual union

[0068] To further investigate the ability of MM-111 to inhibit cell growth when combined with antiestrogens, spheroids of heregulin (HRG)-stimulated BT474-M3 cells were prepared using the method described above or a slight variation thereof and MM-111 was used to -111, tamoxifen, or a combination of MMM-111 and tamoxifen ( Figure 3a ); trastuzumab, tamoxifen, or a combination of trastuzumab and tamoxifen ( Figure 3b ); MM-111, fulvestrant, or a combination of MM-111 and fulvestrant ( Figure 3c ); trastuzumab, fulvestrant, or a combination of trastuzumab and fulvestrant ( Figure 3d ); or MM-111, trastuzumab, or a combination of MM-111 and trastuzumab ( Figure 3e ) dose range to treat spheroids. MM-111 inhibited heregulin-induced spheroid growth but tamoxifen ( Figure 3a ),Trastuzumab( Figure 3b ) and fulvestrant ( Figure 3c ) did not inhib...

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Abstract

Disclosed are methods and compositions for inhibiting the growth of a tumor (e.g., a malignant tumor) in a subject. In particular, combination therapies for treating a tumor in a subject by co-administering either i) an effective amount of an anti-estrogen agent or ii) an effective amount of a receptor tyrosine kinase inhibitor and an effective amount of a bispecific anti-ErbB2 / anti-ErbB3 antibody, and optionally an effective amount of trastuzumab. Also disclosed is a bispecific anti-ErbB2 / anti-ErbB3 antibody for use in the therapy of a tumor in combination with either i) an anti-estrogen agent or ii) a receptor tyrosine kinase inhibitor, and optionally in use with trastuzumab.

Description

technical field [0001] Various aspects of the invention disclosed herein relate to methods and compositions for treating cancer. Background technique [0002] Approximately 75% of breast cancers are estrogen receptor (ER) positive. Other cancers are also ER positive (ER+). Estrogen receptor-mediated intracellular signaling can increase the frequency of cell division and promote tumor growth. Although anti-endocrine therapies such as tamoxifen, fulvestrant, and letrozole have shown remarkable efficacy in the treatment of patients with ER+ breast cancer, inherent resistance to such treatments may be acquired. resistance has limited their success. [0003] The expanding incidence of human epidermal growth factor receptor 2 (HER2, or ErbB2) in breast and other cancers has led to research and development of drugs that target ErbB2 as a therapeutic target. Although both the anti-ErbB2 monoclonal antibody trastuzumab and the ErbB1 / ErbB2 dual receptor tyrosine kinase inhibitor l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/30A61K39/395C12P21/08A61K33/243
CPCA61K39/395A61K39/39558C07K16/32A61K2039/505A61K2039/507C07K2317/622C07K2317/73C07K2319/31A61K31/138A61K31/337A61K31/4196A61K31/517A61K31/565A61K31/7068A61K45/06A61P35/00A61P43/00A61K33/243A61K2300/00A61K33/24C07K16/30C12P21/00A61K39/3955
Inventor 张波查尔洛特·麦克唐纳格亚历山大拉·胡哈洛夫
Owner MERRIMACK PHARMACEUTICALS INC
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