Combination therapy using an anti-egfr agent(s) and igf-1r specific inhibitors

A technology for IGF-1R, an inhibitor, applied in combination with erlotinib, a receptor tyrosine kinase inhibitor, for the treatment of non-small cell lung cancer and other cancers (e.g. field

Inactive Publication Date: 2012-05-16
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Previous attempts to develop effective therapies for NSCLC, particularly erlotinib-resistant cancers, have not been reported

Method used

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  • Combination therapy using an anti-egfr agent(s) and igf-1r specific inhibitors
  • Combination therapy using an anti-egfr agent(s) and igf-1r specific inhibitors
  • Combination therapy using an anti-egfr agent(s) and igf-1r specific inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0217] Example 1 - Correlation between activation of EGFR and IGF1R and efficacy of MK-0646 / erlotinib combination:

[0218] SUMMARY: Activation of multiple receptor tyrosine kinases in cells contributes to resistance to erlotinib. Indeed, activation of EGFR and cMET has been observed in clinical samples from erlotinib-resistant patients.

[0219] Methods: To identify tumors that responded to the MK-0646 / erlotinib combination, the phosphorylation status of different RTKs in a panel of lung cancer cell lines was evaluated. As shown in Figure 1, activated EGFR and IGFlR levels were quantified in a panel of 10 lung cancer cell lines. A few cell lines represented by NCI-H2122 and NCI-H322M exhibited high levels of P-IGF1R and P-EGFR, while the EGFR mutant cell line HCC827 exhibited high levels of P-EGFR with little or no IGF1R activation.

[0220] Briefly, all NSCLC cell lines were obtained from ATCC and maintained in DMEM or RPMI with 10% FBS as directed by ATCC. Approximately...

Embodiment 2

[0221] Example 2 - Inhibition of PI3K and RAS-MAPK Signaling by the MK-0646 / Erlotinib Combination

[0222] SUMMARY: To test the inhibitory effect of these RTKs on PI3K and RAS-MAPK pathway activity, the phosphorylation status of key nodes in the pathway was measured. Such as figure 2 As shown, combined inhibition of EGFR and IGF1R can more effectively block the PI3K pathway, as measured by a substantial reduction in P-S6RP and P-S6K in the NCI-H2122 and NCI-H322M cell lines, which express High levels of both receptors. In cell lines with low levels of P-EGFR and P-IGF1R, this synergistic inhibition of PI3K signaling was not observed (A427 is shown as an example). In other cell lines, similar results were obtained (data not shown).

[0223] Methods: For Western blot analysis, total protein lysates from cells (~300,000) cultured in 6-well plates and stained with Deforolimus (10 nM) or MK- 0646 (10ng / ml) or a combination of the two were treated for 4 hours. Samples were sub...

Embodiment 3

[0224] Example 3 - Functional Effects of Inhibiting EGFR and IGF-1R Signaling

[0225] Summary: To test the functional effect of inhibiting EGFR and IGF1R signaling, growth inhibition under adherent (2D) and non-adherent (3D) conditions was evaluated. Under adherent growth conditions, no significant growth inhibition was observed in MK-0646-treated cell lines. This is consistent with previous experiments (data not shown). To test the effect of this combination under 3D non-adhesive conditions, the inventors developed an ultra-low-adhesion plate-based proliferation assay. Only 7 / 10 cell lines grew measurably when cultured under non-adherent conditions and were used for sensitivity assessment. Under non-adherent conditions, NCI-H2122 cells exhibited a substantial increase in sensitivity to the erlotinib / MK-0646 combination. On the other hand, A427 cells with low levels of P-IGF1R and EGFR showed no significant growth inhibition under 2D or 3D growth conditions.

[0226] Meth...

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Abstract

The combination of an IGF-1R antagonist such as a humanized antibody and an anti-proliferative drug is described. In a preferred embodiment, the present invention describes the combination of an IGF-1R antibody and an anti-proliferative drug belonging to the EGFR-inhibitor class, which is preferably erlotinib. The combination according to the present invention is useful for the treatment of tumours, including IGF-1R and / or EGFR mediated or dependent tumours.

Description

technical field [0001] The present invention relates to methods and compositions for enhancing antitumor activity in mammals. More specifically, the present invention relates to combinations comprising an antibody that specifically binds human IGF-IR and a receptor tyrosine kinase inhibitor. In particular, the invention relates to combination therapy for the treatment of non-small cell lung cancer and other cancers (eg, pancreatic cancer) by administering an IGF-IR antibody and a tyrosine kinase inhibitor, especially erlotinib. Methods and pharmaceutical compositions comprising the combinations or agents may result in better inhibition of tumor cell proliferation than that observed with each individual therapeutic agent, resulting in a more effective treatment than administration of the individual components alone . A specific aspect provides the treatment of erlotinib-resistant lung cancer. Background technique [0002] Lung cancer is the cause of the majority of cancer ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K31/517
CPCA61K39/395A61K45/06A61K31/517A61P35/00A61P43/00A61K2300/00
Inventor S.萨思亚纳拉亚南S.凯西巴特拉C.温特M.查斯坦
Owner SCHERING AG
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