Methods and compositions for use of growth factor antibodies in combination with non-tyrosine targeting kinase inhibitors
The disclosure relates to methods for treating cancer. More particularly, the disclosure relates to use of chimeric non-natural synthetic proteins, in combination with non-tyrosine targeting kinase inhibitors (NTKIs), in treating cancer and preventing intrinsic and/or acquired resistance to NTKIs.
1 . A method of treating non-small cell lung carcinoma (NSCLC) or colorectal cancer (CRC) in a subject, comprising the steps of:
administering to the subject a non-tyrosine targeting kinase inhibitor (NTKI) that inhibits one or more kinases involved in intracellular signaling initiated by epidermal growth factor (EGF), and a non-natural synthetic polypeptide (NNSP), wherein the NNSP comprises a polypeptide comprising an amino acid sequence at least 95% identical to SEQ ID NO: 7 or SEQ ID NO: 8,
an immunogenic polypeptide comprising a cholera toxin B (CT-B) protein, or a fragment thereof, and
a linker, wherein the NNSP is separated from the immunogenic polypeptide by the linker optionally wherein the NNSP is from a cell that expresses SEQ ID NO: 7 or SEQ ID NO: wherein administration of the NNSP induces an immune response against EGF and reduces EGF-mediated receptor signaling, thereby delaying acquisition of resistance to the NTKI in the subject.
2 . The method of claim 1 , wherein the NNSP comprises SEQ ID NO: 2 or SEQ ID NO: 6, or wherein the NNSP is produced by a cell expressing SEQ ID NO: 2 or SEQ ID NO: 6.
3 . The method of claim 1 , wherein the NTKI is Trametinib, Taselisib, Alpelisib, Copanlisib, Idealisib, Duvelisib, Buparlisib, Umbralisib, PX-866, Dactolisib, CUDC-907, Voxtalisib (SAR245409, XL765) ME-401, IPI-549, SF1126, INK1117 Pictilisib, XL147 (SAR245408), GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL 263, RP6503, GNE-477 AEZS-136, Encorafenib, Vemurafenib, Dabrafenib, GDC-0879, PLX-4720, Cobimetinib, Binimetinib, Selumetinib, PD-325901, PD035901, CI-1040, TAK-733, Perifosine, Palomid 529 or pharmaceutically acceptable salts thereof.
4 . The method of claim 1 , wherein the linker is selected from the group
consisting of SSG, GSSG (SEQ ID NO: 9), SSGGG (SEQ ID NO: 10), SGG, GGSGG (SEQ ID NO: 11), GGGGS (SEQ ID NO: 12), SSGGGSGG (SEQ ID NO: 13), SSGGGGSGGG (SEQ ID NO: 14), TSGGGSG (SEQ ID NO: 15), TSGGGGSGG (SEQ ID NO: 16), SSGGSGGGSG (SEQ ID NO: 17), SSGGGSGGSSG (SEQ ID NO: 18), GGSGGTSGGGSG (SEQ ID NO: 19), SGGTSGGGGSGG (SEQ ID NO: 20), GGSGGTSGGGGSGG (SEQ ID NO: 21), SSGGGGSGGGSSG (SEQ ID NO: 22), SSGGGSGGSSGGG (SEQ ID NO: 23), and SSGGGGSGGGSSGGG (SEQ ID NO: 24), optionally wherein the linker is GSSG (SEQ ID NO: 9).
5 . The method of claim 1 , wherein the antibody is administered at about 0.01-0.1 μg/kg to about 95 mg/kg body weight; or from about 0.1-1.0 μg/kg to about 90 mg/kg body weight; or from about 0.5-5.0 μg/kg to about 80 mg/kg body weight; or from about 1.0-10.0 μg/kg to about 60 mg/kg body weight; or from about 5.0-20.0 μg/kg to about 50 mg/kg body weight; or from about 20-50 μg/kg to about 25 mg/kg body weight; or from about 50-100 μg/kg to about 20 mg/kg body weight, In other embodiments this dose may be about 1, 5, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 μg/kg body weight.