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A mistletoe compound made by recombinant technology
Unique effect on ribosomes
Immune stimulation as an additional effect
Effect on metastases
Clinical development

A mistletoe compound made by recombinant technology

Aviscumine (CY-503), the most advanced product of CYTAVIS, is based on a lectin found in the mistletoe plant. Lectins are sugar-binding proteins or glycoproteins which bind with high specificity to sugar molecules, e.g. on the surface of cells. They typically play a role in biological recognition phenomena: As an example, some bacteria use lectins to attach themselves to the cells of the host organism during infection. Aviscumine is a dimeric protein in which one domain, the so-called B-chain, binds to the surface of a target cell while the other, the A-domain, is a strong cytotoxic unit due to its enzymatic activity.

Unique effect on ribosomes

The B-chain binds to an epitope (CD75s) that usually is overexpressed on tumor cells, so that Aviscumine has a strong binding preference. Once it is bound to a tumor cell, the binding leads to the internalization of the molecule, i.e. Aviscumine enters the cell via endocytosis. Thereby, the cytotoxic A-chain acts like a Trojan horse. Once inside the cell, the A-domain starts acting and modifies ribosomal RNA (as a so-called type II ribosome-inactivating protein, or RIP) – see graph.

The modification leads to an irreversible, complete disruption of protein synthesis in the cell (inactivation of translation). This sudden blockage of a vital process triggers a strong cellular stress response, which in turn leads to the induction of apoptosis, the programmed death of the cell.
The blockage of protein production by ribosome inactivation is a cytotoxic mechanism unique to Aviscumine. Most other cytotoxic drugs work by either damaging DNA or by interfering with mRNA.

Immune stimulation as an additional effect

However, Aviscumine has yet another mechanism of action. In picomolar concentrations and administered subcutaneously, it acts as an immune stimulant. It leads to the release of cytokines - mediators of the immune system - and the expression of cytokine receptors (e.g. IL-2Rα) involved in responses of the complex network of the immune system against tumor cells. Aviscumine also activates natural killer (NK) cells and primes neutrophils. Preliminary data already indicate that it may serve as a widely applicable anticancer compound by activating the immune system and by overcoming tumor-induced immunosuppression.

Effect on metastases

Numerous experiments with cancer cell lines and animal models of solid tumors have proven both the cytotoxic and the cytostatic effects of CY-503 (Aviscumine), i.e. its ability to destroy cancer cells or inhibit their growth.

As an example, the effect of CY-503 on metastatic melanoma cells have been evaluated in a cooperation of CYTAVIS Biopharma GmbH and Cellvax-Pharma (France) using the B16-F10 melanoma mouse model, a model widely used for evaluating the anti-metastatic activities of cancer drug candidates.

The study demonstrated excellent tolerability of the compound and a pronounced effect on lung metastases. Efficacy in terms of significant reduction in the number of lung metastases was observed at a dose of 3 ng/kg body weight as compared to placebo.

Clinical development

CY-503 (Aviscumine) has demonstrated excellent safety and tolerability in various Phase I clinical studies involving more than 80 cancer patients. A Phase II study in patients with metastatic melanoma has been completed in summer 2010 and is currently being evaluated. A further Phase II study of CY-503 in patients suffering from metastatic colorectal cancer is presently conducted in more than 20 German study centers and will be expanded to Austria soon. A list of the participating study centers in Germany and further information on the study which is still recruiting patients, is available here.