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Methods and compositions for inhibition of egf/egfr pathway in cobination with anaplastic lymphoma kinase inhibitors

A technology of inhibitors and protocols, applied in drug combinations, chemical instruments and methods, anti-animal/human immunoglobulins, etc., can solve problems such as patient relapse

Pending Publication Date: 2021-06-18
ИН3БАЙО ЛТД
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite the efficacy of second-generation ALK inhibitors, patients almost always relapse
[0012] Although several new approaches are aimed at overcoming various resistance mechanisms developed in ALK-positive NSCLC, including knowledge-based alternating and sequential use of different ALK inhibitors, and combination therapies targeting ALK+ alternative signaling pathways, new approaches are still needed Tackling drug resistance

Method used

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  • Methods and compositions for inhibition of egf/egfr pathway in cobination with anaplastic lymphoma kinase inhibitors
  • Methods and compositions for inhibition of egf/egfr pathway in cobination with anaplastic lymphoma kinase inhibitors
  • Methods and compositions for inhibition of egf/egfr pathway in cobination with anaplastic lymphoma kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0193] Example 1: Effects of combined use of ALK inhibitors and anti-EGF antibodies in non-small cell lung cancer cell lines.

[0194] Compared with EGFR-mutant patients treated with EGFR-TKI, patients treated with ALK-TKI achieved longer progression-free survival. Clinically, 20-30% of patients develop resistance rapidly, but it is unknown whether these patients develop resistance or never respond. The role of circulating EGF in these patients is unclear. The present invention proposes the effect of EGF on TKI resistance using two cell lines containing major ALK rearrangements in NSCLC patients.

[0195] The combination of the BVN22E antibody with the following ALK-TKIs—crizotinib, alectinib, and Brigantinib—was tested on two cell lines harboring major ALK rearrangements in NSCLC patients. An ALK "rearrangement" refers to a series of different mutations. These cell lines such as figure 1 Shown: H3122 lung adenocarcinoma, which contains EML4-ALK fusion variant v1, and H222...

Embodiment 2

[0209] Example 2: Evaluation of the combined use of anti-EGF antibodies and trametinib in BRAF and KRAS mutant cell lines.

[0210] Colorectal cancer (CRC) is not only one of the most common neoplastic cancers, but also presents particular challenges in terms of treatment. Clinically, CRC patients without KRAS mutations can receive EGF-targeted therapies such as cetuximab and erlotinib. However, a large proportion of CRC patients have KRAS mutations, BRAF mutations, or PIK3CA mutations. There are currently no effective treatments for these patients. Chemotherapy and angiogenesis-targeted therapy are commonly used treatments, but they also have significant drawbacks.

[0211] To begin to address the therapeutic needs of CRC patients with KRAS, BRAF, or PIK3CA mutations, in vitro assays of EGF antibodies in combination with the MEK inhibitor trametinib were performed in cell lines with the aforementioned mutations. All experiments were performed in combination with BVN22E ant...

Embodiment 3

[0231] Example 3: Serum evaluation of patients vaccinated with EGF cancer vaccine in SW900 cells.

[0232] The effect of anti-EGF serum from a human patient (22180004) on pEGFR in SW900 wild-type cells in the presence of EGF was observed. 2a = patient before vaccination, 3d = patient after vaccination. In the presence of anti-EGF serum, complete inhibition of pEGFR activation was observed, along with some reduction in pERK1 / 2, see Figure 70 . The effect of human patient anti-EGF serum on pEGFR was observed in SW900 wild-type cells in the presence of EGF in two additional patients, see Figure 71 . Significant inhibition of pEGFR and pERK1 / 2 activation was observed in patient 27030004, while lesser inhibition of pEGFR and pERK1 / 2 was observed in patient 29080005. The anti-EGF serum results of the other three patients were as follows: Figure 72 shown. Significant inhibition of pEGFR and pERK1 / 2 signaling was observed for two of these patients (29040007 and 3308020). For...

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Abstract

A method of treating patients suffering from cancers driven by deregulated Human Epidermal Growth Factor Receptor (HER1 / Human EGFR) comprising administering to a patient in need of such treatment a flexible and active regimen for combining Anaplastic Lymphoma Kinase Inhibitors (ALK Inhibitors) and anti-EGF antibodies for inhibition of the pathway activated by EGF-EGFR binding (mAb). The anti-EGF antibodies can be produced by active immunization or provided passively by the administration of antibodies that are anti-EGF. The method comprises ALK Inhibitors administered according to a continuous regimen based on an average daily dose in the range of 10 to 250 mg and the mAb is co-administered either actively or passively according to a dosing regimen achieving a therapeutic effective amount repeated thrice, twice or once a week, once in two weeks, once in three weeks or at least once monthly.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Patent Application No. 62 / 715,351, filed August 7, 2018, U.S. Provisional Patent Application No. 62 / 727,056, filed September 5, 2018, 62 / 727,056, filed October 22, 2018 U.S. Provisional Patent Application No. 748,772, U.S. Provisional Patent Application No. 62 / 760,529, filed November 13, 2018, and U.S. Provisional Patent Application No. 62 / 822,290, filed March 22, 2019, wherein the U.S. The contents of the Provisional Patent Application are hereby incorporated by reference in their entirety for all purposes. technical field [0003] Some embodiments of the invention are directed to methods of treatment and prevention of disorders such as cancer, particularly in individuals who have developed drug resistance or are unresponsive to treatment with anaplastic lymphoma kinase inhibitors (ALK inhibitors). Background technique [0004] Non-small-cell lung cancer (NSCLC) is the leading...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00A61P35/00C07K16/00A61K39/395A61K31/4545A61K31/506A61K31/5377A61K31/675
CPCA61K39/001131A61K2039/86A61P35/00C07K16/22A61K39/3955A61K2039/545A61K2039/55A61K45/06A61K31/4545A61K31/506A61K31/675A61K31/5377A61K2300/00A61K31/519A61K2039/505
Inventor 埃里克·东特米格尔·安格尔·莫利纳-维拉
Owner ИН3БАЙО ЛТД
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