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HPV Antibodies May Become Cancer Biomarkers With New Protein Array Technology

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NEW YORK (GenomeWeb) –A team from Arizona State University's Biodesign Institute has developed a customizable, array-based approach to studying the body's immune response to human papillomavirus.

By detecting antibodies targeting proteins in the HPV subtypes most highly associated with cancers, the technology could help create a new class of diagnostic and prognostic biomarkers for diseases that can take years to develop.

Led by senior author Karen Anderson and first author Radwa Ewaisha, the scientists described their HPV immunoprofiling protein array earlier this month in Proteomics.

The technology generates proteins using mammalian translational machinery from full-length cDNA plasmid vectors fixed to the glass slide, which are captured by anti-tag antibodies at addressable locations.

"When we say programmable, it's because we can make it again and change the DNA at each spot," Anderson told GenomeWeb. "That's the power of it. Anything for which we can get the gene we can put into this system and over 90 percent of [human] genes will express well in this approach."

The method provides a way to measure antibody responses to several subtypes of HPV simultaneously, from very little serum.

"We can start to understand association of the immune response to the progression of the patient's disease," Anderson said. That's important because while HPV is associated in almost all cases of cervical cancer, there are other cancers where the association is less well understood, like anogenital and oropharyngeal (head and neck) cancers. "We're particularly interested in whether the antibody response can be used for diagnosis and monitoring," she said. Although oropharyngeal cancers are on the rise and they are also highly associated with particular subtypes of HPV, there is no equivalent to a Pap smear to predict cancer risk in patients.

"It's harder to get to abnormal cells in the throat because of the location," Anderson said. "Nucleic acid screening may be useful for this, but it's not just about viral infection, it's about viral persistence and causing changes that leads to cancer. Its finding those changes in the virus and in the host that's important."

While almost every human gets infected by HPV at some point, most can clear the virus. But some don't and viral persistence is associated with cancer risk. What the difference is between these groups of people in terms of their immune system, their genetics, or some other differential factor that prevents some to clear the virus remains a fundamental question of cancer immunology, Anderson said. Seeing the antibodies generated against HPV proteins, even if it's only part of the immune response, may provide a window into understanding how that response begins. "But to really be able to measure antibody responses to those viruses, we needed to develop newer ways to display the proteins formed from a broader collection of the high-risk subtypes of the virus," Anderson said.

While there are over 150 subtypes of HPV, a few such as subtypes 16 and 18 are highly associated with cancer risk. While cervical cancers are almost always associated with HPV, they can be associated with a greater diversity of HPV subtypes than, say, oropharyngeal cancers, which are primarily associated with HPV16.

While HPV16 and HPV18 are implicated in about 80 percent of the HPV-associated cancers, there are another dozen or so high-risk subtypes.

Anderson's goal is to develop ways to measure antibody responses across many viral types in several cancers, but in particular she's interested in cervical disease.

Her approach has been to create in vitro displays of proteins on different surfaces to attract antibodies against those proteins.

The new study describes a method to look at almost 100 different proteins from several high-risk HPV subtypes. The array described presented eight proteins from 10 high-risk subtypes and two low-risk subtypes.

"We demonstrated protein expression was robust for almost all of these proteins … reproducible between the arrays, and that we could detect antibodies both specifically using panels of monoclonal antibodies and using [patient] sample serum to detect these antibodies that are bound," Anderson said.

The array technology has a couple advantages. First is the mammalian transcription and translation, which may maintain structural epitopes that the antibodies recognize. The other is that it is highly customizable and flexible.We can go from a gene [of interest] to a functional assay for measuring antibody response very quickly," Anderson said.

Anderson's group had previously only looked at HPV16 but this new array broadened the scope of HPV subtypes.

She hopes the arrays will enable new studies like the one she's doing to look at antibody responses to women with both pre-invasive and invasive cervical cancer.

Anderson, who serves on the scientific advisory board of Provista Diagnostics, said the firm has been evaluating the set of antibody biomarkers for licensing. Her lab has previously licensed biomarkers for breast and ovarian cancer to the firm.

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