Compositions and methods for detecting cancer

Abstract

The invention provides sialylated glycans and antibodies that specifically bind to them. The invention's compositions and methods for using them are useful for early detection and diagnosis of cancer.

Description

[0001]This application claims priority to co-pending U.S. provisional Application Ser. No. 61 / 295,386, filed Jan. 15, 2010, which is herein incorporated by reference in its entirety for all purposes.[0002]This invention was made with government support under grant U01 CA128442-01, awarded by the National Institutes of Health (NIH) and HHSN261200700063C awarded by National Cancer Institute Small Business Invention Research (NCI SBIR). The government has certain rights in the invention.FIELD OF INVENTION[0003]The invention provides sialylated glycans and antibodies that specifically bind to them. The invention's compositions and methods for using them are useful for early detection and diagnosis of cancer.BACKGROUND[0004]Cancer is a leading cause of death worldwide, and mortality is largely attributed to cancers of epithelial origin, i.e., carcinomas of the lung, colon, breast, liver, stomach, prostate, ovary, endometrium and pancreas (Parkin et al., 2001). Survival rates are dramatic...

AI Technical Summary

Benefits of technology

[0057]The terms “reduce,”“inhibit,”“diminish,”“suppress,”“decrease,” and grammatical equivalents (including “lower,”“smaller,” etc.) when in reference to the level of any molecule (e.g., amino acid sequence, and nucleic acid sequence, glycan, Neu5Gc-sialylated antigen (e.g., sialylated glycan), epitope of a Neu5Gc-sialylated antigen, derivative of a Neu5Gc-sialylated antigen, antibody (e.g., that specifically binds to one or more of a Neu5Gc-sialylated antigen, epitope of a eu5Gc-sialylated antigen, derivative of a Neu5Gc-sialylated antigen), etc.), cell, and / or phenomenon (e.g., disease symptom, binding to a molecule, specificity of binding of two molecules, affinity of binding of two molecules, specificity to cancer, sensitivity to cancer, affinity of binding, enzyme activity, etc.) in a first sample (or in a first subject) relative to a second sample (or relative to a second subject), mean that the quantity of molecule, cell and / or phenomenon in the first sample (or in the first subject) is lower than in the second sample (or in the second subject) by any amount that is statistically significant using any art-accepted statistical method of analysis. In one embodiment, the quantity of molecule, cell and / or phenomenon in the first sample (or in the first subject) is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than, and / or at least 90% lower than the quantity of the same molecule, cell and / or phenomenon in the second sample (or in the second subject). In another embodiment, the quantity of molecule, cell, and / or phenomenon in the first sample (or in the first subject) is lower by any numerical percentage from 5% to 100%, such as, but not limited to, from 10% to 100%, from 20% to 100%, from 30% to 100%, from 40% to 100%, from 50% to 100%, from 60% to 100%, from 70% to 100%, from 80% to 100%, and from 90% to 100% lower than the quantity of the same molecule, cell and / or phenomenon in the second sample (or in the second subject). In one embodiment, the first subject is exemplified by, but not limited to, a subject that has been manipulated using the invention's compositions and / or methods. In a further embodiment, the second subject is exemplified by, but not limited to, a subject that has not been manipulated using the invention's compositions and / or methods. In an alternative embodiment, the second subject is exemplified by, but not limited to, a subject to that has been manipulated, using the invention's compositions and / or methods, at a different dosage and / or for a different duration and / or via a different route of administration compared to the first subject. In one embodiment, the first and second subjects may be the same individual, such as where the effect of different regimens (e.g., of dosages, duration, route of administration, etc.) of the invention's compositions and / or methods is sought to be determined in one individual. In another embodiment, the first and second subjects may be different individuals, such as when comparing the effect of the invention's compositions and / or methods on one individual participating in a clinical trial and another individual in a hospital.

[0059]Reference herein to any numerical range expressly includes each numerical value (including fractional numbers and whole numbers) encompassed by that range. To illustrate, and without limitation, reference herein to a range of “at least 50” includes whole numbers of 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, etc., and fractional numbers 50.1, 50.2 50.3, 50.4, 50.5, 50.6, 50.7, 50.8, 50.9, etc. In a further illustration, reference herein to a range of “less than 50” includes whole numbers 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, etc., and fractional numbers 49.9, 49.8, 49.7, 49.6, 49.5, 49.4, 49.3, 49.2, 49.1, 49.0, etc. In yet another illustration, reference herein to a range of from “5 to 10” includes each whole number of 5, 6, 7, 8, 9, and 10, and each fractional number such as 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, etc.

[0060]The term “control” as used herein when in reference to a sample, cell, tissue, animal, etc., refers to any type of sample, cell, tissue, animal, etc. that one of ordinary skill in the art may use for comparing the results to another sample, cell, tissue, animal, etc., by maintaining the same conditions except in some one particular factor, and thus inferring the causal significance of this varied factor.BRIEF DESCRIPTION OF THE INVENTION

[0061]The invention provides the discovery that when Neu5Gc replaces Neu5Ac in any sialylated antigen that is over-expressed in a human cancer, this generates a novel cancer-specific antigen and cancer-specific antibody response. Thus, the invention provides the discovery that cancer is correlated with replacement of naturally occurring Neu5Ac in any sialylated antigen, that is over-expressed in a human cancer, by Neu5Gc.

[0062]Thus, the invention provides cancer markers exemplified by a) Neu5Gc-sialylated antigens, b) epitopes of the Neu5Gc-sialylated antigens, c) derivatives of the Neu5Gc-sialylated antigen, and d) antibodies that specifically bind to one or more of the antigen, the epitope, and the derivative. The invention further provides methods for detecting cancer by detecting one or more of these cancer markers, such as by detecting antibody that specifically binds to one or more of the antigen, the epitope, and the derivative, and to the antibodies against these markers.

Problems solved by technology

Some well-known biomarkers (Nossov et al., 2008, Candefjord et al., 2009, Greene et al., 2009, Gupta and Lis, 2009, Nelson et al., 2009a, Nogueira et al., 2009, van Leeuwen et al., 2009) are reliably detected in advanced stages of disease, but lack sufficient sensitivity and especially specificity for early cancer diagnosis, and are thus used mainly for prognosis, staging, monitoring and selection of therapy (Ludwig and Weinstein, 2005).

However, specificity and sensitivity have been limited mainly owing to the heterogenous nature of cancer, where different proteins are aberrantly processed or regulated in patients with the same type of cancer, causing much variability in the immune response (Raedle et al., 1998, Soussi, 2000, Tan et al., 2009).

Available blood based assays have minimal clinical utility for the early diagnosis of cancer due to poor sensitivity and specificity.

None of these tests has been shown to reduce cancer specific mortality with a reasonable financial or morbidity cost.

For example: in cancer screening tests of human subjects, it is undesirable to risk falsely identifying healthy people as having cancer (low specificity), due to the high costs.

These costs are both physical (unnecessary risky procedures) and financial.

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