The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

The present invention provides a compound exemplified by Formula I: ##STR00001##
a process for its preparation and the use of a medicament for the treatment of cancer. The compound of the present invention has an inhibitory effect on various cancer cells and can be biologically converted into the active drug Linifanib in vitro (in liver homogenate and spleen homogenate) to inhibit the proliferation of tumor cells, especially liver cancer cells, at a lower dose.

A number of anti-angiogenic strategies connected with the VEGF signalling pathway are used in current clinical treatment or trial phase, but they either cause adverse effects or are not specific. Various strategies were aimed at identifying peptides inhibiting the VEGF-A.sub.165/NRP-1 interaction. A well-known antiangiogenic peptide is the heptapeptide termed “A7R” having the amino acid sequence ATWLPPR, for which various derivatives have been synthesized, which include peptides having the general sequence Lys(hArg)-AA.sup.2-AA.sup.3-Arg. However, the ability of the known peptides to inhibit the VEGF-A.sub.165/NRP-1 interaction was too low for their use as candidate drugs for inhibiting angiogenesis in subjects in need thereof. The present inventors have now conceived a family of novel peptide-like compounds having a nanomolar affinity for NRP-1, which are thus endowed with a powerful capacity to inhibit the VEGF-A.sub.165/NRP-1 interaction. These novel peptide-like compounds may be relevantly used as antiangiogenic compounds, especially in subjects affected with cancer.

A number of anti-angiogenic strategies connected with the VEGF signalling pathway are used in current clinical treatment or trial phase, but they either cause adverse effects or are not specific. Various strategies were aimed at identifying peptides inhibiting the VEGF-A.sub.165/NRP-1 interaction. A well-known antiangiogenic peptide is the heptapeptide termed “A7R” having the amino acid sequence ATWLPPR, for which various derivatives have been synthesized, which include peptides having the general sequence Lys(hArg)-AA.sup.2-AA.sup.3-Arg. However, the ability of the known peptides to inhibit the VEGF-A.sub.165/NRP-1 interaction was too low for their use as candidate drugs for inhibiting angiogenesis in subjects in need thereof. The present inventors have now conceived a family of novel peptide-like compounds having a nanomolar affinity for NRP-1, which are thus endowed with a powerful capacity to inhibit the VEGF-A.sub.165/NRP-1 interaction. These novel peptide-like compounds may be relevantly used as antiangiogenic compounds, especially in subjects affected with cancer.

The subject invention provides compounds, peptidomimetics, and methods of synthesis thereof. The subject invention provides the synthesis and use of guanidino acids and/or poly guanidino acids not only as vehicles for drug delivery but as toolbox for drug discovery. The peptidomimetic of the subject invention comprises oligo(guanidino acid)s or poly(guanidino acid)s with guanidines as peptide bond surrogates. The incorporation of the guanidine as amide bond surrogates offers significant differences in polarity, hydrogen bonding capability, and acid-base character.

Interferon-γ-inducible protein 10 (IP-10) peptides, IP-10 peptide variants and in silico designed C-X-C chemokine receptor 3 (CXCR3) peptide agonists are described. The small peptides can be used for inhibiting pathological tissue remodeling and treating fibrosis in a subject, such as a subject with fibrosis of the heart, lung, liver, kidney or skin. The peptide agonists can also be used to treat cardiovascular disease, including myocardial infarction and ischemia-reperfusion injury. Also described are in silico designed peptide antagonists that bind CXCR3 or ligands of CXCR3. These antagonist peptides block CXCR3 signaling by disrupting interaction of CXCR3 with its ligand. Antagonist peptides can be used, for example, to treat myocarditis and atherosclerosis. In additional embodiments agonists and antagonists of CXCR4 are disclosed.

Interferon-γ-inducible protein 10 (IP-10) peptides, IP-10 peptide variants and in silico designed C-X-C chemokine receptor 3 (CXCR3) peptide agonists are described. The small peptides can be used for inhibiting pathological tissue remodeling and treating fibrosis in a subject, such as a subject with fibrosis of the heart, lung, liver, kidney or skin. The peptide agonists can also be used to treat cardiovascular disease, including myocardial infarction and ischemia-reperfusion injury. Also described are in silico designed peptide antagonists that bind CXCR3 or ligands of CXCR3. These antagonist peptides block CXCR3 signaling by disrupting interaction of CXCR3 with its ligand. Antagonist peptides can be used, for example, to treat myocarditis and atherosclerosis. In additional embodiments agonists and antagonists of CXCR4 are disclosed.

A method of treating a patient who has hepatocellular carcinoma (HCC), colorectal carcinoma (CRC), glioblastoma (GB), gastric cancer (GC), esophageal cancer, NSCLC, pancreatic cancer (PC), renal cell carcinoma (RCC), benign prostate hyperplasia (BPH), prostate cancer (PCA), ovarian cancer (OC), melanoma, breast cancer (BRCA), CLL, Merkel cell carcinoma (MCC), SCLC, Non-Hodgkin lymphoma (NHL), AML, gallbladder cancer and cholangiocarcinoma (GBC, CCC), urinary bladder cancer (UBC), and uterine cancer (UEC) includes administering to said patient a composition containing a population of activated T cells that selectively recognize cells in the patient that aberrantly express a peptide. A pharmaceutical composition contains activated T cells that selectively recognize cells in a patient that aberrantly express a peptide, and a pharmaceutically acceptable carrier, in which the T cells bind to the peptide in a complex with an MHC class I molecule, and the composition is for treating the patient who has HCC, CRC, GB, GC, esophageal cancer, NSCLC, PC, RCC, BPH, PCA, OC, melanoma, BRCA, CLL, MCC, SCLC, NHL, AML, GBC, CCC, UBC, and/or UEC. A method of treating a patient who has HCC, CRC, GB, GC, esophageal cancer, NSCLC, PC, RCC, BPH, PCA, OC, melanoma, BRCA, CLL, MCC, SCLC, NHL, AML, GBC, CCC, UBC, and/or UEC includes administering to said patient a composition comprising a peptide in the form of a pharmaceutically acceptable salt, thereby inducing a T-cell response to the HCC, CRC, GB, GC, esophageal cancer, NSCLC, PC, RCC, BPH, PCA, OC, melanoma, BRCA, CLL, MCC, SCLC, NHL, AML, GBC, CCC, UBC, and/or UEC.

A method of treating a patient who has hepatocellular carcinoma (HCC), colorectal carcinoma (CRC), glioblastoma (GB), gastric cancer (GC), esophageal cancer, NSCLC, pancreatic cancer (PC), renal cell carcinoma (RCC), benign prostate hyperplasia (BPH), prostate cancer (PCA), ovarian cancer (OC), melanoma, breast cancer (BRCA), CLL, Merkel cell carcinoma (MCC), SCLC, Non-Hodgkin lymphoma (NHL), AML, gallbladder cancer and cholangiocarcinoma (GBC, CCC), urinary bladder cancer (UBC), and uterine cancer (UEC) includes administering to said patient a composition containing a population of activated T cells that selectively recognize cells in the patient that aberrantly express a peptide. A pharmaceutical composition contains activated T cells that selectively recognize cells in a patient that aberrantly express a peptide, and a pharmaceutically acceptable carrier, in which the T cells bind to the peptide in a complex with an MHC class I molecule, and the composition is for treating the patient who has HCC, CRC, GB, GC, esophageal cancer, NSCLC, PC, RCC, BPH, PCA, OC, melanoma, BRCA, CLL, MCC, SCLC, NHL, AML, GBC, CCC, UBC, and/or UEC. A method of treating a patient who has HCC, CRC, GB, GC, esophageal cancer, NSCLC, PC, RCC, BPH, PCA, OC, melanoma, BRCA, CLL, MCC, SCLC, NHL, AML, GBC, CCC, UBC, and/or UEC includes administering to said patient a composition comprising a peptide in the form of a pharmaceutically acceptable salt, thereby inducing a T-cell response to the HCC, CRC, GB, GC, esophageal cancer, NSCLC, PC, RCC, BPH, PCA, OC, melanoma, BRCA, CLL, MCC, SCLC, NHL, AML, GBC, CCC, UBC, and/or UEC.