PEPperPRINT and PROGEN to develop novel RA test

SeroRA antigen library will reportedly enable superior rheumatoid arthritis biomarker screening

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HEIDELBERG, Germany—Biotech company PEPperPRINT GmbH announced in early June its intent to develop a novel biomarker test for the early and differentiated diagnosis of rheumatoid arthritis (RA), together with fellow German company PROGEN Biotechnik GmbH, also based in Heidelberg. The German Federal Ministry of Education and Research (BMBF) approved funds of €600,000 in the next three years for this joint development.
RA is the most common inflammatory rheumatoid disease, affecting approximately 20 million people worldwide. An early diagnosis and targeted therapy within the first two years is pivotal to avoid joint damage and deformation that may lead to physical impairments and/or disability.
Dr. Volker Stadler, CEO of PEPperPRINT, says, “Current RA blood tests rely on the detection of rheumatoid factor or antibodies against citrullinated peptides such as anti-CCP, an artificial marker peptide, or citrullinated vimentin (anti-MCV). However, many other antigenic proteins are associated with RA which are not addressed by these tests. Moreover, there is still an incomplete picture of the underlying peptide epitopes, including post-translationally modified variants.”
“The lack of more comprehensive and sensitive seromarkers can be attributed to the previously available library sizes for the screening of RA epitope biomarkers, and to an incomplete coverage of posttranslational modifications,” Stadler continues. “Our new approach based on the SeroRA library covers more than 120,000 different peptides derived from protein antigens linked to RA. The size of our SeroRA peptide microarray library exceeds that of other RA antigen libraries by several orders of magnitude. The library covers not only several tens of thousands of native peptides, but also the corresponding citrullinated and—for the very first time—homocitrullinated and mixed citrullinated/homocitrullinated variants. Particularly, homocitrullinated peptides were recently identified as a key determinant for the binding of autoantibodies in RF and anti-CCP-negative RA patients. This powerful system enables the identification of completely new serum biomarkers and biomarker combinations for meaningful RA in-vitro (IVD) and companion diagnostics.”
Stadler says, “By taking these advantages into account, we’re very confident that we will identify serum biomarkers or biomarker combinations for a novel serological RA test that reaches a sensitivity of at least 90 percent in an early disease phase. Since an early diagnosis and targeted therapy within the first two years is pivotal to the outcome of the disease, we think that such a new RA test will substantially improve patient care in rheumatoid diseases.”
The sensitivity of existing serological tests is currently in the range of 70 percent, which means that about 30 percent of RA patients are declared seronegative and are not correctly diagnosed according to their individual antibody profile. One major goal of this project is the identification of a highly sensitive and RA-specific biomarker set that enables a clear serological diagnosis in the early phases of the disease with regard to complex and heterogeneous antibody profiles. The identification of individual RA-specific biomarkers plays a central role in patient stratification as a basis for timely and personalized therapy decisions.
“Citrulline is a post-translational modification of arginine, and homocitrulline of lysine. Citrullinations and homocitrullinations of native proteins often occur under inflammatory conditions and can turn native proteins into antigens that provoke autoimmune responses,” explains Stadler, adding that citrullinated peptides or proteins are particularly found in rheumatoid arthritis and, accordingly, antibodies against anti-CCP and anti-MCV are frequently used in the standard RA tests.
“During the last years, homocitrullinated peptides and proteins were also identified as key autoantigens for rheumatoid arthritis, although the data basis is significantly less comprehensive compared to citrullinated peptides,” he continues. “To our knowledge, a broad library screening for antibodies against homocitrullinated peptides (anti-CarP antibodies) has not been performed yet, not to mention combinations of citrulline and homocitrulline in a single peptide.”
The new test will most likely not only include novel citrullinated peptides, but also homocitrullinated variants, Stadler notes.
When asked about the genesis of PEPperPRINT and PROGEN’s collaboration, he told DDNews, “We were looking for a diagnostic company that can help us develop a new IVD test for rheumatoid arthritis, particularly with a focus on the regulatory topics. PROGEN's people are experts in the development of IVDs, and since our labs are located very close to each other, it was obvious [we’d] ask PROGEN if they wanted to join this project. The company is well experienced in any aspect of diagnostic test development and, as a subsidiary of R-Biopharm, part of one of the bigger diagnostic companies in Germany. I personally happen to know Sven Kuhlendahl, who has been the general manager of PROGEN for many years, so there was a great deal of mutual confidence. [The companies] haven’t worked together before, although we often discussed possible projects.”
For test design, PEPperPRINT will utilize its new microarray-based SeroRA library with more than 120,000 linear and cyclic constrained peptide antigens of human and pathogen origin to screen for IgG and IgA antibody profiles in serum samples of RA patient collectives.
“The screening has already begun, and the initial data look very promising. We hope that we will be able to present first data as early as October at an autoimmunity conference in Germany,” says Stadler.
As part of the collaboration, PROGEN will carefully validate the biomarker candidates and will use the final peptide selection to establish and optimize a sandwich-assay standard format for IVD purposes according to regulatory requirements. Dr. Sven Kuhlendahl, general manager of PROGEN, said, “We look forward to utilizing our longstanding expertise in immunochemistry for the development of a novel assay that enables the early diagnosis of RA with superior sensitivity and specificity.”
With PEPperPRINT’s proprietary peptide laser printing technology, its high-density peptide microarrays set a new standard in terms of peptide diversity, data quality and content flexibility, Stadler maintains, reportedly enabling the generation of any peptide microarray with more than 1,000 different peptides per square centimeter within a time frame of four weeks, “without a need for an expensive peptide pre-synthesis in uniquely high quality.” This peptide laser printing technology is also the basis for the new SeroRA library, he notes.
“Moreover, PEPperPRINT is well experienced in microarray-based immunoassays, with several hundreds to thousands of samples tested each year and numerous biomarker discovery projects. This is combined with PROGEN’s long term expertise in the development of IVD tests and an in-depth knowledge on market needs and regulatory requirements. We are linking a state-of-the art microarray technology with fundamental diagnostic expertise,” Stadler concludes.

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