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Science - Discovery
Oncofetal Chondroitin Sulfate: a novel cancer biomarker
Chondroitin Sulfate (CS) is a linear chain composed of alternating disaccharide units (GalNAc and GlcA), which is present as a secondary, post-translational modification to proteoglycans. During oncogenesis, a distinct form known as oncofetal CS emerges, characterized by its extended chain length and a heavy sulfation.
With over 15 years of research by our team and collaborators, we have demonstrated the promise of oncofetal CS as a next-generation molecular target for cancer diagnostics, supported by five unique characteristics:
- Immune evasion and growth promotion: Oncofetal CS plays a crucial role in enabling tumors to evade the immune system and supporting cancer cell growth, establishing it as a key target in oncogenesis.
- Prevalence: Oncofetal CS is present in 95% of all tested cancers, underscoring its broad applicability as a universal cancer biomarker.
- Specificity: Oncofetal CS is largely absent from healthy or inflamed tissue, with the exception the placenta, ensuring a high level of specificity in distinguishing malignant from benign.
- Significant Overexpression in Tumors: Oncofetal CS is highly overexpressed and broadly distributed in tumors, constituting up to 1% of total tumor mass, marking it as a substantial and detectable target.
- Circulation: Oncofetal CS is not only found on the surface of cancer cells, but also in free circulating forms, making it accessible for detection by minimal invasive measures such as a blood draw.
Representative human tissue samples stained for oncofetal CS and cell nuclei
The road to discovering and targeting oncofetal CS
Oncofetal CS was originally known as fetal CS in the context of placental malaria, where it was identified as a critical molecule. Over the years, we and others uncovered that fetal CS supports the rapid growth of the placenta and plays a key role in immune regulation by shielding the fetus from the maternal immune system. These biological functions are strikingly similar to the mechanisms driving cancer progression.
The malaria parasite employs specialized proteins to survive in the human host. One of these proteins – called VAR2CSA – allows the malaria parasite to avoid splenic clearance by binding to fetal CS in the placenta. In 2012, we took a leap of faith and mixed malaria parasites with cancer cells. To our surprise, the malaria parasites immediately anchored themselves to a wide array of cancer cell lines. Despite the long-established association between CS modifications and oncogenesis, the lack of methods to differentiate and detect specific CS forms has hindered their investigation as potential cancer biomarkers. Our breakthrough discovery unlocked a multi-year research effort, focusing on the exploration of a recombinant version of the malaria protein (rVAR2) as a tool for detecting oncofetal CS. This approach has positioned oncofetal CS as a promising universal cancer biomarker, opening doors to new diagnostic and therapeutic possibilities.
rVAR2 and Vartumabs: Two complementary, high affinity high specificity tools to detect oncofetal CS
The role of oncofetal CS in fetal development is conserved across mammals. This prevented us from developing antibodies through immunization. Our initial diagnostic efforts therefore focused on the use of specific protein domains of VAR2CSA – generally dubbed rVAR2 – which we identified as having high specificity and affinity towards oncofetal CS. With rVAR2, we demonstrated efficient capture and detection of Circulating Tumor Cells from patient samples, and initiated the development of detection methods.
In 2022, we had a breakthrough in our efforts to develop antibodies and generated Vartumabs – our IP-protected portfolio of antibodies with high affinity and exquisite specificity for oncofetal CS. Using Vartumabs, our parent company VAR2Pharma established a pipeline of therapeutic modalities.
At VARCT Diagnostics, we have started developing in vitro assays with Vartumabs side-by-side with rVAR2, setting the stage for highly precise cancer detection.
Representative human tissue samples stained with DAPI and either Vartumabs or an antibody that stains all CS
Vartumabs: Our Cancer Targeting Antibody Platform
In 2022 we embarked on the development of our proprietary platform technology – Vartumabs. Vartumabs are our proprietary antibody/single chain variable fragments portfolio displaying nM affinity and exquisite, targeted specificity towards ofCS. We demonstrated their unique targeting properties towards cancer and limited binding to healthy tissue across virtually all tissue types using various in vitro models, including patient needle biopsies and tissue sections.
Based on these results, we have established a pipeline of therapeutic assets.
From Malaria Research to a New Cancer Biomarker
The malaria parasite hides inside human red blood cells. To avoid spleen clearance, it expresses proteins on the surface of infected erythrocytes to enable adherence to host endothelial receptors. Millions of years of evolution resulted in a protein dubbed VAR2CSA, responsible for anchoring the malaria parasite to distinct chondroitin sulfate (CS) glycosaminoglycan chains only present in the placenta. In this way, the parasite hides in the placenta of pregnant women, evading circulation and the immune system.
We and others discovered that this CS sugar mediates the extreme growth (of placenta and fetus) and plays a critical role keeping the immune system away from the fetus. As shared features with cancer, we took a leap of faith and mixed malaria parasites with cancer cells. To our surprise, the malaria parasites (↑ in Figure) rapidly anchored themselves to the different cancers as though these were the placenta.
Malaria parasites (↑) binding various cancer cell lines
Oncofetal Chondroitin Sulfate: an omnipresent, tumor-agnostic cancer biomarker
CS are glycosaminoglycans found on proteoglycans, proteins present on cell surfaces. While CS modifications on proteoglycans have been described as contributing to oncogenesis, the sheer heterogeneity of CS molecules (for example the chain length, number and location of sulfation) and lack of appropriate reagents had prevented stronger correlations between CS type and cellular phenotypes.
Representative human tissue samples stained for ofCS and DAPI (cell nucleus)
By using the recombinant malaria VAR2CSA protein, we and collaborators demonstrated that the (now dubbed) oncofetal CS (ofCS) is expressed in over 30 different cancers with limited presence in healthy tissue beyond the placenta. Further studies revealed additional fundamental characteristics of ofCS, including being a long chain CS with a specific hybrid chondroitin sulfation pattern, and that therapeutic approaches based on this malaria protein could cure cancer in animal models.
Vartumabs: Our Cancer Targeting Antibody Platform
In 2022 we embarked on the development of our proprietary platform technology – Vartumabs. Vartumabs are our proprietary antibody/single chain variable fragments portfolio displaying nM affinity and exquisite, targeted specificity towards ofCS. We demonstrated their unique targeting properties towards cancer and limited binding to healthy tissue across virtually all tissue types using various in vitro models, including patient needle biopsies and tissue sections.
