BR-112018001679-B1 - METHOD FOR PREDICTING WHETHER A PATIENT SUFFERING FROM PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) WILL BE RESPONSIVE TO TREATMENT WITH NIMOTUZUMAB AND GENCITABINE

BR112018001679B1BR 112018001679 B1BR112018001679 B1BR 112018001679B1BR-112018001679-B1

Abstract

METHOD FOR TREATING A POPULATION OF PATIENTS, COMPOSITION, MONOCLONAL ANTIBODY, METHOD FOR PREDICTING WHETHER A PATIENT SUFFERING FROM PANCREATIC DUCTAL ADENOCARCINOMA WILL BE UNRESPONSIVE TO TREATMENT WITH AN ANTIBODY, AND METHOD FOR TREATING A POPULATION OF PATIENTS. The present invention relates to the field of cancer immunotherapy, in particular pancreatic ductal adenocarcinoma (PDAC). More specifically, the present invention provides means and methods for treating a population of PDAC patients suffering from PDAC tumors expressing KRAS, HRAS, or NRAS wild-type antigens. The means and methods of the invention involve administering an anti-EGFR antibody, antigen-binding fragment, or peptide thereof to patients. Means and methods for selecting patients and tumors based on their responsiveness to treatment are also provided in the present application. The present invention relates to the field of cancer immunotherapy, in particular pancreatic ductal adenocarcinoma (PDAC). More specifically, the present invention provides means and methods for treating a population of PDAC patients suffering from PDAC tumors expressing KRAS, HRAS, or NRAS wild-type. The means and methods of the invention involved administering an anti-EGFR antibody, binding fragment (...).

Inventors

Dirk STRUMBERG
Sara DE DOSSO
Michael Kneba
Suayib YALCIN
Friedrich OVERKAMP
Frank SCHLEGEL
Markus DOMMACH
Robert ROHRBERG
Tilman STEINMETZ
BACH FERDINAND
Dirk Reuter
Beate SCHULTHEIS
RIKRIK ASIYAH ILYAS
NORMANDO E. IZNAGA ESCOBAR
MATTHIAS P. EBERT
Jens SIVEKE
Andrea KERKHOFF
Ralf HOFHEINZ
DIRK M. BEHRINGER
WOLFGANG E. SCHMIDT
Erdem GOKER

Assignees

ONCOSCIENCE AG
INNOCIMAB PTE LTD

Dates

Publication Date: 20260310
Application Date: 20160727
Priority Date: 20150727

Claims (2)

1. METHOD FOR PREDICTING WHETHER OR NOT A PATIENT SUFFERING FROM PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) WILL BE RESPONSIVE TO TREATMENT WITH NIMOTUZUMAB AND GENCITABINE, characterized by comprising determining the presence of a KRAS mutation in an in vitro sample of PDAC tumor from the patient; wherein the presence of the KRAS mutation in an in vitro sample of the tumor indicates that the patient will be non-responsive to treatment with nimotuzumab and gemcitabine, wherein the KRAS mutation is preferably at the codon of one or more amino acid residues G12, G13, Q61, A146 or D154 of SEQ ID NO. 7 or SEQ ID No. 24.
2. METHOD, according to claim 1, characterized by determining the presence of a KRAS mutation in an in vitro PDAC tumor sample comprising amplifying a KRAS nucleic acid from an in vitro tumor sample and sequencing the nucleic acid and/or comprising detecting the mutant KRAS polypeptide in an in vitro tumor sample.

Description

BACKGROUND OF THE INVENTION [001] Pancreatic cancer is the fourth leading cause of cancer death, with approximately 48,960 new cases (3% of all new cancer cases) and about 40,560 (6.9% of all cancer cases) estimated deaths in the United States in 2015. Most cases (about 99%) occur in the exocrine component of the pancreas. There are several subtypes of exocrine pancreatic cancer, but their diagnosis and treatment have much in common. The small minority of cancers that arise in the endocrine tissue of the pancreas have different clinical characteristics. Both groups primarily (but not exclusively) affect people over 40 years of age and are slightly more common in men, but some rare subtypes occur primarily in women or children. [002] Pancreatic cancer is aggressive, with few symptoms until the cancer is in an advanced stage. Symptoms may include abdominal pain, weight loss, diarrhea, and jaundice. Pancreatic cancer has a very poor prognosis, as it is usually diagnosed at a late stage when the cancer is already locally advanced or has spread to other parts of the body. [003] Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer, accounting for about 85% of all pancreatic cancers. It is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite intensive treatment. The overall 5-year survival rate of only 5% has remained unchanged over the past 30 years, despite enormous efforts in preclinical and clinical science. [004] Ras proteins are proto-oncogenes that are frequently mutated in human cancers. They are encoded by three ubiquitously expressed genes: HRAS, KRAS, and NRAS. Recent exome sequencing has established that KRAS is the most frequently mutated gene in PDAC (95%). The three human RAS genes, HRAS, NRAS, and KRAS, encode four highly homologous (83–90% sequence identity) small 21 kDa GTPases that cycle between a GTP-bound “on” state and a GDP-bound “off” state, regulating pathways responsible for cell proliferation and survival (Bryant et al. Trends Biochem Sci. February 2014; 39(2): 91–100). Ras proteins are normally tightly regulated by guanine nucleotide exchange factors (GEFs) that promote dissociation to GDP and binding to GTP, and GTPase-activating proteins (GAPs) that stimulate the intrinsic GTPase activity of Ras to switch off signaling. Abnormal Ras function is associated with hyperproliferative developmental dysfunctions and cancer. Activation of KRAS mutations found in human PDAC (point mutations at codon G12 (98% of all KRAS mutations in PDAC), G13, and Q61) impairs KRAS inactivation, thus leading to constitutive KRAS activation and persistent stimulation of downstream signaling pathways that drive many of the characteristics of cancer, sustained proliferation, metabolic reprogramming, anti-apoptosis, remodeling of the tumor microenvironment, evasion of the immune response, cell migration, and metastasis (Eser et al. Br J Cancer. August 26, 2014; 111(5): 817-22). Importantly, KRAS mutation is also an early and initiating event, as over 90% of low-grade pancreatic intraepithelial neoplasias (PanIN) have been shown to harbor oncogenic KRAS mutations (Bryant et al., loc. cit.). It was also discovered that activating HRAS mutations in human PDAC (point mutations at codon G12D, 49.7% (1312 mutations out of 2639 tumor samples) and at codon G12V, 30.8% (812 mutations out of 2639 tumor samples)) are associated with this mutation. The Catalogue of Somatic Mutations in Cancer (COSMIC), which represents the most comprehensive database on mutations in human tumors currently available (Forbes S.A. et al. Nucleic Acids Res. 2011, 39 (Database issue): D945-950), despite its relatively small sample size, revealed strong trends indicating that KRAS is the most frequently mutated isoform in pancreatic cancer with 61% of mutations (3127 mutations in 5169 tumor samples), followed by NRAS with 2% of mutations (5 mutations in 248 tumor samples) and HRAS with 0% (no mutations were found in 248 tumor samples). 221 tumor samples). [005] To date, surgery is the only cure for pancreatic cancer and, in particular, PDAC. However, surgery is indicated in only about 20% of new cases. The current standard of care for PDAC patients also includes gemcitabine, a nucleoside analogue that, without additional surgery, only prolongs survival by a few weeks. The FOLFIRINOX chemotherapy regimen using four drugs has been found to be more effective than gemcitabine, but has substantial side effects. This is also true for protein-bound paclitaxel (nab-paclitaxel) (von Hoff et al. N Engl J Med. October 31, 2013; 369(18): 1691-703). [006] Due to considerable experimental evidence for the role of mutant KRAS and HRAS as drivers of cancer development and growth in a large subpopulation of PDAC patients, there have been extensive efforts to develop direct inhibitors of KRAS or HRAS. However, all clinical attempts to directly interfere with KRAS or HRAS activity h