218P - Exploiting a unique glycosaminoglycan for novel pan-cancer therapies and diagnostics

Background

Aberrant glycosylation patterns can be found on a range of different proteins in the tumor and therefore offer promising targets for cancer therapy and diagnostic. In line with this, we have previously found that a specific glycosaminoglycan named oncofetal chondroitin sulfate (ofCS) is overexpressed in cancers compared to healthy tissue. ofCS is a unique tumor-specific glycosylation biomarker due to its omnipresence in malignant tissue and its essential role in promoting tumor growth, migration, and immune evasion.

Methods

This study builds on the unique finding that a recombinant malaria protein (rVAR2) mimics the evolutionary refined malaria parasite binding to ofCS. Using rVAR2-isolated ofCS and phage-display panning, we developed two monoclonal antibodies (Vartumabs), which shows similar high specificity and nanomolar affinity towards ofCS.

Results

rVAR2 and Vartumabs showed robust in vitro binding to cancer cells independent of tissue origin but limited binding to normal white blood cells, enabling the ofCS-based detection of rare circulating tumor cells from patient blood samples. In addition to cell surface binding, in vitro tissue staining demonstrated binding to ofCS in the tumor stroma, whereas minimal binding was observed to normal, benign, or inflamed tissue. Furthermore, elevated levels of ofCS-modified proteins could be detected in urine, cerebrospinal, and plasma samples from cancer patients. Intravenous injection of the antibodies in animal models resulted in specific localization to tumors. Antibody drug conjugates (ADC) showed a high, often curative, therapeutic response in a wide range of animal models including allograft, xenograft, and PDX animal models with no evident signs of toxicity. Importantly, the ADC induced immunogenic cell death, and single low dose administration in combination with a check point inhibitor resulted in complete cure in allograft models.

Conclusions

We present the identification and characterizations of two first in class anti-ofCS antibodies that can be functionalized for diagnostic and therapeutic targeting of cancer. First clinical studies in a basked trial of patients with solid tumors will commence in Q3 2024.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

VAR2 Pharmaceuticals, VarCT Diagnostics, Lundbeck Foundation, Innovation Fund Denmark, the National Key Research and Development Program of China, the Fundamental Research Funds for the Central Universities of China, NIH Prostate Cancer PNW-SPORE, the Canadian Institutes of Health Research (CIHR), Novo Nordisk Foundation, and Carlsberg Foundation.

Disclosure

M. Ø. Agerbæk: Financial Interests, Personal, Full or part-time Employment: VarCT Dignostics; Financial Interests, Personal, Stocks/Shares: Var2 Pharmaceuticals. E.E. Vidal-Calvo: Financial Interests, Personal, Full or part-time Employment: Var2 Pharmaceuticals. A. Salanti: Financial Interests, Personal, Stocks/Shares: Var2 Pharmaceuticals. All other authors have declared no conflicts of interest.