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Combination of a c-Met antagonist and an aminoheteroaryl compound for the treatment of cancer

A technology of aminoheteroaryl and composition, applied in the field of treating mammalian cancer, can solve problems such as increasing the complexity of cell function

Active Publication Date: 2015-05-27
PIERRE FABRE MEDICAMENT SAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Additionally, a unique aspect of c-Met signaling relative to other RTKs is its reported association with focal adhesion complexes and non-kinase binding partners such as α6β4 integrins [Trusolino L, Bertotti A, Comoglio PM , Cell.2001, 107:643-54], CD44v6 [Van der Voort R, Taher TE, Wielenga VJ, Spaargaren M, Prevo R, Smit L, David G, Hartmann G, Gherardi E, Pals ST, J Biol Chem. 1999, 274(10):6499-506], Plexin B1 or semaphorins [Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM, Nat Cell Biol.2002, 4(9 ):720-4; Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PM, Bussolino F, Giordano S, Blood.2005, 105(11):4321-9; Conrotto P, Corso S, Gamberini S , Comoglio PM, Giordano S, Oncogene.2004, 23:5131-7], which further increases the complexity of the regulation of cellular functions by this receptor

Method used

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  • Combination of a c-Met antagonist and an aminoheteroaryl compound for the treatment of cancer
  • Combination of a c-Met antagonist and an aminoheteroaryl compound for the treatment of cancer
  • Combination of a c-Met antagonist and an aminoheteroaryl compound for the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Example 1: In vivo activity of 224G11 and PF-02341066 as monotherapy

[0120] To demonstrate that a laboratory-available in vivo model of NCI-H441 is sensitive to both the 224G11 antibody and the PF-2341066 compound, immunocompromised mice implanted subcutaneously with NCI-H441 were used. Briefly, NCI-H441 NSCLC cells from ATCC were cultured in RPMI 1640 medium, 10% FCS, 1% L-glutamine. Cells were split two days prior to implantation so that they were in logarithmic growth phase. Ten million NCI-H441 cells were injected subcutaneously into athymic nude mice. Five days after implantation, tumors were detectable and animals were divided into groups of 6 mice with comparable tumor sizes. For antibody treatment, mice were treated intraperitoneally with a loading dose of 2 mg 224G11 Mab / mouse, followed by 1 mg antibody / mouse twice a week. 50 mg / kg of PF-02341066 was given p.o. (oral gavage) daily for one week, followed by a double dose of the fifth day dose for 5 days a...

Embodiment 2

[0122] Example 2: In vivo activity of the combination of 224G11 and PF-02341066

[0123] NCI-H441 cells from ATCC were routinely cultured in RPMI 1640 medium, 10% FCS, 1% L-glutamine. Cells were split two days prior to implantation so that they were in logarithmic growth phase. Ten million NCI-H441 cells were transplanted into athymic nude mice. Five days after implantation, tumors were measurable and animals were divided into groups of 6 mice with comparable tumor sizes. For antibody treatment, mice were treated intraperitoneally with a loading dose of 2 mg 224G11 Mab / mouse, followed by 1 mg antibody / mouse twice a week. PF-2341066 was administered daily p.o. (oral gavage) at 50 mg / kg for one week, followed by a double dose of the fifth day dose for 5 days a week. Groups of mice receiving both 224G11 and PF-2341066 were treated in the same manner as described above for each compound. The tumor volume was measured twice a week and calculated by the formula: π / 6×length×wid...

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PUM

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Abstract

The invention also relates to a composition comprising an antibody antagonist to c-Met and an aminoheteroaryl compound, particularly as a medicament. The present invention also comprises a pharmaceutical composition comprising said anti c-Met antibody and said aminoheteroaryl compound as combination products for simultaneous, separate or sequential use. The invention relates to the use of the composition of the invention for the treatment of cancer in a mammal.

Description

technical field [0001] The present invention relates to compositions comprising antibody antagonists of c-Met, in particular as medicaments, and aminoheteroaryl compounds. The present invention also encompasses a pharmaceutical composition comprising said anti-c-Met antibody and said aminoheteroaryl compound as a combined preparation for simultaneous, separate or sequential use. The present invention relates to the use of a composition of the invention for the treatment of cancer in a mammal. Background technique [0002] c-Met is a prototypical member of the RTK subfamily that also includes RON and SEA. The c-Met RTK family is structurally distinct from other RTK families and is the only known high-affinity receptor for hepatocyte growth factor (HGF), also known as scater factor (SF) [D.P.Bottaro et al. Human, Science 1991, 251: 802-804; L. Naldini et al., Eur. Mol. Biol. Org. J. 1991, 10: 2867-2878]. c-Met and HGF are ubiquitously expressed in various tissues, and their...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K39/395A61K31/435A61P35/00
CPCA61K31/435A61K39/39558C07K16/2863C07K2317/73C07K2317/76A61K31/4545A61P35/00A61K2300/00A61K39/3955
Inventor L·格奇
Owner PIERRE FABRE MEDICAMENT SAS