IP Library › Granted Patent US 12,595,297
Granted Patent B2
US 12,595,297 · App. 15/073,021 · Granted Apr 7, 2026

Methods and compositions for inhibition of EGF/EGFR pathway in combination with tyrosine kinase inhibitors

Inventors: Erik D'Hondt (Bazel, BE); Miguel Ángel Molina Vila (Badalona, ES)
Assignee: In3Bio Ltd.
C07K16/22A61K31/506A61K31/517A61K31/5377A61K31/7084A61K39/00A61K39/001104A61K39/001131A61K39/3955A61K45/06A61K2039/545C07K2317/76
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Quick Facts
Patent No.
US 12,595,297
App. No.
15/073,021
Granted
Apr 7, 2026
Kind
B2
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 a tyrosine kinase inhibitor (TKI) 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 TKI administered according to a continuous regimen based on an average daily dose in the range of 10 to 150 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.

Claims (9)

1 . A method of treating non-small cell lung cancer (NSCLC) in a patient suffering from NSCLC associated with one or more Epidermal Growth Factor Receptor (EGFR) mutations and increased levels of STAT3 activation, comprising:

identifying the patient as having the NSCLC associated with one or more EGFR mutations and increased levels of STAT3 activation;

administering to the patient an immunogenic polypeptide selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2 according to an effective amount to inhibit the EGF/EGFR pathway in the NSCLC of the patient; and

administering to the patient an effective amount of a tyrosine kinase inhibitor (TKI), wherein the TKI is selected from the group consisting of gefitinib, erlotinib, afatinib, dacomitinib, and pharmaceutically acceptable salts thereof, or the TKI is selected from the group consisting of 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl) prop-2-en-1-one, WZ 3146, WZ 4002, WZ 8040, and pharmaceutically acceptable salts thereof, or the TKI is selected from the group consisting of a quinazoline, a pyridopyrimidine, and a pyrrolopyrimidine;

wherein administration of the immunogenic polypeptide with the TKI reduces STAT3 activation, thereby treating the NSCLC associated with one or more EGFR mutations and increased levels of STAT3 activation of the patient.

2 . The method of claim 1 , wherein the TKI is administered according to a continuous regimen based on an average daily dose in the range of 10 mg to 150 mg, and the immunogenic polypeptide is administered twice or once a week or once in two weeks to the patient, wherein the NSCLC of the patient has acquired resistance to treatment with TKIs selected from the group consisting of gefitinib, erlotinib, afatinib, and dacomitinib.

3 . The method of claim 1 , wherein the effective amount of the TKI is an average daily dose in the range of 10 mg to 150 mg.

4 . The method of claim 1 , wherein the immunogenic polypeptide is administered thrice, twice, or once a week, once in two weeks, once in three weeks or at least once a month to the patient.

5 . The method of claim 1 , wherein the one or more Epidermal Growth Factor Receptor (EGFR) mutations is T790M.

Assignments (4)
SECURITY INTEREST Recorded Feb 4, 2026
From: IN3BIO LTD.
To: WITHERS BERGMAN LLP
Reel/Frame 074607/0289 →
CHANGE OF NAME Recorded Aug 2, 2019
From: BIOVEN 3 LTD.
To: IN3BIO LTD.
Reel/Frame 049940/0607 →
SECURITY INTEREST Recorded Sep 7, 2018
From: BIOVEN 3 LTD.
To: INNOCORP VENTURES SDN. BHD.; HALFMOON BAY CAPITAL LTD
Reel/Frame 046814/0374 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 24, 2016
From: D'HONDT, ERIK; VILA, MIGUEL ÁNGEL MOLINA
To: BIOVEN 3 LIMITED
Reel/Frame 039001/0682 →
Continuity (2)
Provisional Application 62160183 · May 12, 2015
Related Publication 20160333087A1 · Nov 17, 2016
References Cited (55)
US 8828391B2 · Denis · 2014 [cited by examiner]
US 20060251654A1 · Casimiro et al. · 2006 [cited by applicant]
US 20120294867A1 · Louis et al. · 2012 [cited by applicant]
CN 103533961A · 2014 [cited by applicant]
CN 104066447A · 2014 [cited by applicant]
JP 2014513706B2 · 2014 [cited by applicant]
JP 2014534258B2 · 2014 [cited by applicant]
KR 1020140031903A · 2014 [cited by applicant]
KR 1020140108235A · 2014 [cited by applicant]
WO WO2013076580A2 · 2013 [cited by examiner]
Niu et al., In vitro human cell line models to predict clinical response to anticancer drugs. Pharmacogenomics 2015; 16(3): 273-285. [cited by examiner]
Regales et al., Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest. 119:3000-3010, 2009. [cited by examiner]
Goldberg et al., Randomized trial of Afatinib plus cetuximab versus Afatinib alone for first-Line treatment of EGFR-mutant non-small-cell lung cancer: final results from SWOG S1403. J Clin Oncol 38:4076-4085, 2020. [cited by examiner]
Wu et al. Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells Oncotarget. Dec. 2013; 4(12): 2430-2438. (Year: 2013). [cited by examiner]
Bowie et al. Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions. Science, 1990 (Year: 1990). [cited by examiner]
Burgess et al. Possible Dissociation of the Heparin-binding and Mitogenic Activities of Heparin-binding (Acidic Fibroblas) Growth Factor-1 from Its Receptor-binding Activities by Site-directed Mutagenesis of a Single Ly… [cited by examiner]
Lazar et al. Transforming Growth Factor alpha: Mutation of Aspartic Acid 47 and Leucine 48 Results in Different Biological Activities. Mol. Cell. Biol. 1988 (Year: 1988). [cited by examiner]
Whisstock et al. Prediction of protein function from protein sequence and structure. Quarterly Reviews in Biophysics. 2007 (Year: 2007). [cited by examiner]
Lee et al. Treatments for EGFR-mutatnt non-small lung cancer (NSCLC): The road to a success, paved with failured. 2017 (Year: 2017). [cited by examiner]
Oronsky et al. Navigating the “No Man's Land” of TKI-Failed EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC): A Review. 2018 (Year: 2018). [cited by examiner]
Lee et al. Treatments for EGFR-mutant non-small lung cancer (NSCLC): The road to a success, paved with failure. 2017 (Year: 2017). [cited by examiner]
Vinageras et al. Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer. J. Clin. Oncol. 26:1452-1458, 2008 (Year: 2008). [cited by examiner]
Jian Y. Cheng et al.CIMAvax EGF vaccine for stage IIIb/IV non-small cell lung carcinoma 11, Human Vaccines & Immunoth Erapeutics, vol. 8, no. 12, Dec. 1 2012 (2012-12-01), pages 1799-1801. [cited by applicant]
Database EMBASE [Online] Elsevier Science Publishers, Amsterdam NL; August 2009 (2009-08)9 LIUD ET AL: “Inhibitory effect of gefitinib combined with DNA vaccine targeting EGFR against mouse lung cancer Lewis cells” XP00… [cited by applicant]
D V Parums: “Status of inmune therapy in Non-Small Cell Lung Cancer (NSCLC)”, Drugs of the Future 9 1 Jul. 2014 (2014-07-01)9 pages 469-4779. [cited by applicant]
Sugiura, M. et al. Lung Cancer Vaccine Therapy, Lung Cancer Society vol. 49, 2009. [cited by applicant]
Kim, H. et al. Combined Lapatinib and Cetuximab Enhance Cytotoxicity Against Gefitinib—Resistant Lung Cancer Cells, Molecular Cancer Therapeutics, 2008. [cited by applicant]
Office Action in corresponding Russian Application 2017143182 dated Mar. 26, 2020. [cited by applicant]
Office Action in corresponding Japanese Application 2017-559450 dated Jun. 9, 2020. [cited by applicant]
First Office Action issued in corresponding Chinese Application No. 201680038424, dated Jul. 6, 2020 (6 pages), and English translation thereof (9 pages). [cited by applicant]
Vinageras et al. Phase II Randomized Controlled Trial of an Epidermal Growth Factor Vaccine in Advanced Non-Small Cell Lung Cancer. J. Clin. Oncol. 26: 1452-1458, 2008. [cited by applicant]
Wolf et al. Attenuated Endocytosis and Toxicity of a Mutant Cholera Toxin with Decreased Ability to Cluster Ganglioside GM1 Molecules. Infect Immun. 76(4):1476-1484, 2008. [cited by applicant]
Chiu, HC, et al. Suppression of Stat3 activity sensitizes gefitinib-resistant non small cell lung cancer cells. Biochemical Pharmacology. Jun. 1, 2011. [cited by applicant]
Wang, M., et al. Combined Erlotinib and Cetuximab overcome the acquired resistance to epidermal growth factor receptors tyrosine kinase inhibitor in non-small-cell lung cancer. Journal of Cancer Research and Clinical On… [cited by applicant]
Examination Report in corresponding Australian application No. 2016259868 dated Aug. 30, 2021. [cited by applicant]
Decision on Rejection in corresponding Chinese application No. 201680038424.4 dated Sep. 1, 2021. [cited by applicant]
Zhong, et al. Immunotherapy: How to Apply to Lung Cancer? Progress in Internal Medicine of Oncology in China—Collection of Essays on Education of Chinese Oncologists. Jul. 2014. [cited by applicant]
Office Action in corresponding Brazil application No. BR112017024073-4 dated Sep. 13, 2021. [cited by applicant]
Bowie et al. Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions. Science, 1990. [cited by applicant]
Burgess et al. Possible Dissociation of the Heparin-binding and Mitogenic Activities of Heparin-binding (Acidic Fibroblas) Growth Factor-1 from Its Receptor-binding Activities by Site-directed Mutagenesis of a Single Ly… [cited by applicant]
Lazar et al. Transforming Growth Factor alpha: Mutation of Aspartic Acid 47 and Leucine 48 Results in Different Biological Activities. Mol. Cell. Biol. 1988. [cited by applicant]
Whisstock et al. Prediction of protein function from protein sequence and structure. Quarterly Reviews in Biophysics. 2007. [cited by applicant]
Oronsky et al. Navigating the “No Man's Land” of TKI-Failed EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC): A Review. 2018. [cited by applicant]
Lee et al. Treatments for EGFR-mutatnt non-small lung cancer (NSCLC): The road to a success, paved with failured. 2017. [cited by applicant]
Dipa Patel et al.: “Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation”. Jan. 1, 2009. [cited by applicant]
Jiang et al. Correlation of activate STAT3 expression with clinicopathologic features in lung adenocarcinoma and squamous cell carcinoma. 2011. [cited by applicant]
Looyenga et al. STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma. [cited by applicant]
[cited by applicant]
[cited by applicant]
Bork, “Powers and Pitfalls in Sequence Analysis: The 70% Hurdle”, Genome Research, vol. 10, 2000, pp. 398-400. [cited by applicant]
Defeo-Jones et al., “Substitution of Lysine for Arginine at Position 42 of Human Transforming Growth Factor-a Eliminates Biological Activity without Changing Internal Disulfide Bonds”, Molecular and Cellular Biology, Se… [cited by applicant]
Punta et al., “The Rough Guide to In Silico Function Prediction, or How To Use Sequence and Structure Information To Predict Protein Function”, PLoS Comput. Biol., vol. 4, No. 10: e1000160, 2008. [cited by applicant]
Song et al., “A Single Amino Acid Change (Asp 533Ala53) Converts Survivin from Anti-apoptotic to Pro-apoptotic”, Molecular Biology of the Cell, vol. 15, Mar. 2004, pp. 1287-1296. [cited by applicant]
Beatriz Garcia et al., ‘Effective Inhibition of the Epidermal Growth Factor/Epidermal Growth Factor Receptor Binding by Anti-Epidermal Growth Factor Antibodies Is Related to Better Survival in Advanced Non-Small-Cell Lu… [cited by applicant]
Office Action in corresponding Korean application No. 10-2017-7035561 dated Jul. 14, 2023. [cited by applicant]