Detection of serum-derived antibodies against microbial antigens is routinely used for the diagnosis and prognosis of some infectious diseases. In the past 10 years, strong evidence has emerged to support the theory that the human immune system also mounts spontaneous humoral responses against autologous tumor-associated antigens (TAA). Up to now, there are at least 1800 TAA identified based on recognition by antibodies present in patients sera. These TAA include targets from many cancer types, such as melanoma, renal cancer, Hodgkins disease, esophageal cancer, lung cancer, colon cancer, gastric cancer, breast cancer, prostate cancer and so on.The discovery of these TAA awakens the old hope of finding serological markers for cancer detection, diagnosis and prognosis. However, the development of a sensitive, cost effective and comprehensive cancer diagnostic based on serological profiles to TAA has been limited by practical problems. For example, most of the antigens react with few - or no -- allogeneic sera. This indicates that an effective diagnostic for a given cancer must test for the presence of antibodies to a large number of TAA associated with that cancer. Such a test would require the recombinant production and purification of multiple TAA proteins, which is expensive and difficult to achieve. Multiplying these problems by each cancer for which a screen is desired makes developing a comprehensive test unfeasible.What is needed is a platform solution that enables the sensitive detection of serum antibodies to multiple TAA for multiple cancers.
The present invention enables the creation of a new product for the detection, prognosis and prediction of multiple cancers based on the simultaneous detection of serum antibodies to multiple TAA. The method bypasses the expensive and difficult requirement for purification of individual recombinant TAA proteins by using chemically synthesized peptides of the TAA. Utilizing prediction software, researchers at UCLA have demonstrated that one can systematically and efficiently predict peptide regions on a TAA that can (1) react to antibodies in a subset of patients with a specific cancer, and (2) effectively distinguish a cancer patient from a negative control as accurately as the recombinant TAA. This approach of using peptide fragments of TAA to detect their corresponding antibodies in a patients serum can be repeated with any number of TAA to create a panel array of synthetic peptide fragments to provide a sensitive and comprehensive test for multiple cancers.
The UCLA researchers have proven the feasibility of the approach by using their prediction software to identify a peptide fragment of NY-ESO-1, a tumor associated antigen highly expressed in different types of cancers. NY-ESO-1-specific antibodies present in the sera of patients with melanoma, prostate cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, and hepatocellular carcinoma reacted with the synthetic peptide at a frequency similar to their reaction with the recombinant protein. This proof-of-principle demonstrates the feasibility of applying the same methodology to multiple TAA to create an entirely new product line of synthetic TAA fragments for the routine detection, prognosis and prediction of multiple cancers.The UCLA investigators would welcome the opportunity to collaborate with an industrial partner for the continued identification and validation of reactive fragments to other TAA. The UCLA researchers can bring to this collaboration two valuable assets: Know-how in identifying peptide fragments for use in serological detection of cancer; and access to clinical samples and clinical data in different cancer indications.
The result achieved on the common antigen NY-ESO-1 serves as a proof-of-principle for detection of antigen fragment from a TAA and further supports antigen based serological detection of cancer. Because only a certain portion of the disease population mounts a response to a specific antigen, other TAA fragments with serological profiles related to the same cancer will need to be identified for the test to be sensitive. For each cancer, it is envisioned that a panel of TAA will be required to accurately identify all individuals that have that cancer. Furthermore, it is believed that several cancers can be detected simultaneously by having antigenic peptide fragments that correspond to the different cancers on the same array.At this stage, the researchers are focusing on targets clinically relevant for prostate cancer, renal cancer, and non-small cell lung cancer. However, the study may be expanded to other forms of cancers as access to appropriate clinical samples is arranged.
|United States Of America||Issued Patent||7,943,729||05/17/2011||2004-496|