Invented by Jean-Pol Cassart, Thierry Coche, Remi M Palmantier, Carlota Vinals Y De Bassols, GlaxoSmithKline Biologicals SA
The GlaxoSmithKline Biologicals SA invention works as followsCompositions and methods are disclosed for the treatment and diagnosis of cancer. This includes lung, colon and colorectal cancers. Illustrative formulations include one or more Cripto tumour polypeptides and immunogenic portions of these polypeptides. They also contain polynucleotides encoding such polypeptides as well as antigen-presenting cells that express such polypeptides. Compositions disclosed are useful for the treatment, diagnosis and prevention of cancers, including lung, colon and colorectal cancer.
Background for Cripto tumor polypeptide
CRIPTO, a 188 aa molecule, shares homologies (EMBO Journal (1989), Vol 8 (7) pp1987-1991) with the EGF family.
huCRIPTO” mRNA can only be detected in undifferentiated mammary epithelial cell. mCRIPTO, however, is present during pregnancy and breastfeeding (inducing branching morphogenesis) and may act as an autocrine factor to promote normal breast tissue. The mouse embryo must have CRIPTO to ensure the correct orientation of its anterior-posterior direction.
The U.S. Patent “Human criptogen has been expressed” No. 5,654,140.
Cancer is an important health problem around the globe. Despite advances in cancer detection and treatment, there is no universally effective method of prevention or treatment. The current therapies, which generally combine chemotherapy, surgery, and radiation, are inadequate for many patients.
Colon cancer is the second-most common cancer in the United States, and the second-most common cause of death from cancer. In 1998, an estimated 95,600 cases of colon carcinoma will have been detected, and there were estimated to be 47,700 deaths. Ninety-two percent of patients who have colorectal carcinoma detected at an early stage are still alive five years later. Unfortunately, only 37 percent of colorectal cases are diagnosed in this stage. The survival stage. The survival stage.
The prognosis for colon cancer depends on the extent of tumour penetration through the bowel, the amount of metastasis and the presence or lack of nodal involvement. Early detection and treatment is therefore crucial. The use of sigmoidoscopy for fecal-occult blood screening, colonoscopy, and double contrast barium is used to aid in diagnosis. The type and stage determine the treatment regimen, which may include radiation therapy, chemotherapy, or surgery. The most common treatment is surgery. However, recurrence after surgery is a serious problem. It is also the cause of many deaths. Despite extensive research on therapies, colon cancer is still difficult to diagnose and treatment. There is therefore a need for improved methods of treating cancers. “The present invention fulfills these needs, and also provides other benefits related to it.
Breast cancer is a major health issue for women throughout the United States, and the rest of the world. Breast cancer is the second most common cause of cancer related deaths among women. It affects more than 180,000 American women each year, despite advances in diagnosis and treatment. The lifetime risk of breast cancer for women in North America is now 1 in 8.
There is no vaccine or universally effective method of prevention or treatment for breast cancer. The management of breast cancer relies on early diagnosis through routine screening procedures and aggressive treatment, which can include surgery, radiotherapy and chemotherapy. Treatment is chosen based on prognostic factors, such as an analysis of tumour markers. Porter-Jordan & Lippman, Breast Cancer 8, 73-100 (1994). The use of established markers can often lead to results that are difficult to interpret. In addition, the high mortality rate observed in patients with breast cancer indicates that there is a need for improvements in the treatment and preventative measures of the disease.
In the United States, lung cancer is the leading cause of cancer-related death for both men and woman. An estimated 172,000 cases were reported in 1994. The 5-year survival rate for all lung cancer patients is 13%, regardless of their state at diagnosis. The five-year survival rates for cases diagnosed while the disease was still localised are 46%. Only 16% of lung tumours are detected before they have spread.
Despite extensive research into treatments for these cancers and others, breast, colorectal, and colon remain difficult to diagnose and effectively treat. There is therefore a need for improved methods of treating and preventing these cancers. “The present invention meets these needs, and also provides other benefits related to them.
In one aspect, this invention provides polynucleotide compounds that contain a sequence chosen from the following:
In another aspect of the invention, polypeptide compositions are provided that contain an amino acid coded by a sequence of polynucleotides described above.
The polypeptides or polynucleotides in the present invention can elicit an immune response. This includes a humoral, cellular, and/or a cellular response. If necessary, these polypeptides are conjugated with a carrier and/or are adjuvanted.
The present invention also provides fragments or variants or derivatives of polypeptide or polynucleotide and/or sequences. These fragments or variants or derivatives have an immunogenic level at least 50%, more preferably 70%, and still more preferably 90%, of the immunogenic level of a sequence of polypeptides set forth by SEQ ID no: 2 or 4, or a sequence of polypeptides encoded by SEQ NO: 1 or 3.
The present invention also provides polynucleotides encoding a polypeptide as described above, expression vectors containing such polynucleotides, and host cells that have been transformed or transfected using such expression vectors.
In other aspects, this invention provides pharmaceutical compositions that contain a polypeptide (or polynucleotide) as described above in combination with a physiologically-acceptable carrier.
In a related aspect, pharmaceutical compositions (e.g. vaccine compositions) are provided for prophylactic and therapeutic purposes. These compositions typically comprise an immunegenic polypeptide, polynucleotide or polynucleotide and an immunostimulant such as an adjuvant.
The present invention also provides pharmaceutical compositions that include: (a), an antigen-presenting cell that demonstrates a polypeptide in the manner described above, and (b), a pharmaceutically accepted carrier or excipient. Antigen-presenting cells that can be used as examples include macrophages (monocytes), dendritics cells, fibroblasts, and B cells.
In related aspects, pharmaceutical compositions that include: (a), an antigen-presenting cell that expresses the polypeptide described above; and (b), an immunostimulant are provided.
The present invention also provides polynucleotides that encode fusion protein compositions comprising at least one polypeptide, such as those described above. These compositions are typically pharmaceutical compositions (e.g. vaccine compositions) and include a physiologically-acceptable carrier or immunostimulant. As described in the present invention, the fusion proteins can comprise multiple immunogenic polypeptides, or portions/variations thereof. They may also include one or more segments of polypeptides to facilitate the expression, purification, and/or immunogenicity.
In further aspects, the invention provides methods to stimulate an immune response in patients, preferably in T cells in human patients, by administering a pharmaceutical formulation described here. The patient could be suffering from lung, colon, colorectal, or breast cancer. In this case, the methods would provide treatment, or a patient at risk of such a condition might be treated as if it were a prophylactic measure. The patient must have a tumour that expresses cripto antigens.
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