Science - Discovery
Oncofetal Chondroitin Sulfate: a novel cancer biomarker
Oncofetal Chondroitin Sulfate (CS) is a linear chain of primarily two specific alternating disaccharide units (GalNAc and GlcA) which displays an unusually long length and with a heavy sulfation pattern.
In healthy tissues, regular CS is present primarily as a secondary, pos-translational modification to some proteoglycans, which are proteins present on cell surfaces. Oncofetal CS emerges in cancer as a result of the activation of immune evasion and growth signals.
Over 15 years of research, we and collaborators have demonstrated that oncofetal CS holds the promise of becoming the next molecular target for cancer therapies due to 5 unique characteristics:
- Key role immune evasion and promoting growth.
- Presence in 95% of all tested cancers.
- Largely absent from healthy or inflamed tissue except the placenta.
- High overexpression in cancer, representing almost 1% of tumour mass.
- Found in free form in the extracellular matrix and in circulation. Found in the membrane of cancer cells and circulating tumor cells. Found to modify various proteins, including proteoglycans which are also found in circulation.
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 when first identified as a key molecule in malaria. The malaria parasite uses special proteins to stay inside the human host. One of these proteins – called VAR2CSA – allows the malaria parasite to hide in the human placenta by binding oncofetal CS. Over the years, we and others showed that oncofetal CS mediates the extreme growth of the placenta and fetus, and is key to maintaining the immune system away from the fetus.
Back in 2012, we took a leap of faith and mixed malaria parasites with cancer cells. To our surprise, the malaria parasites rapidly anchored themselves to the different cancer cell lines. Despite CS modifications being associated with oncogenesis for years, identifying this ubiquitous cancer marker was not possible due to the sheer variety of CS forms and lack of methods to differentiate and detect different forms. This discovery prompted several years of research on using the malaria VAR2CSA protein to study and target oncofetal CS in cancer.
Vartumabs: First-in-Class antibodies against oncofetal CS
The role of oncofetal CS in fetal development is conserved across mammals. This prevented us from developing antibodies through immunization.
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, we established a pipeline of therapeutic modalities, and generated an extensive data package on their unique properties towards oncofetal CS, safety and efficacy across targeted therapy modalities.
Representative human tissue samples stained with Vartumabs, an antibody that stains all CS and DAPI (cell nuclei)
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.