About half of the drugs approved for medical therapy in the last two decades have been derivatives of natural substances. Focused on oncology the proportion is even higher: 74% of all drugs against tumors are of natural origin and derived out of natural molecules or are inspired by them. Some examples are: Vinca alkaloids, taxanes, drugs acting on DNA topoisomerases, cytokines, and different enzymes.
MELEMA will take up that development tradition by focussing on natural molecules with positive effects upon the immune system. MELEMA starts its development with
Aviscumine (ME-503), the most advanced product of MELEMA, is based on a lectin found in the mistletoe plant and is manufactured by recombinant DNA techniques in E. coli.. Lectins are glycoproteins binding selectively to glycoproteins or glycolipids on cell surfaces. The dimeric protein consists of two sub-units: A-chain and B-chain. Whereas the A-chain has the strong cytotoxic attribute, the B-chain acts as a targeting moiety.
Unique action on ribosomes
The B-chain binds to CD75s, an epitope overexpressed on many tumor cells also on antigen-presenting cells (APCs). The binding leads to the internalization of the molecule, i.e. Aviscumine enters the cell via endocytosis. The mechanism reminds of the Trojan horse: Inside the cell, the cytotoxic A-chain acts as a site-specific type II ribosome-inactivating N-glycosidase.
Mode of action of Aviscumine
Aviscumine selectively cleaves the N-glycosidic bond of the adenine-4324 residue in eukaryotic 28S ribosomal RNA leading to a catalytic inactivation of ribosomes that causes the inhibition of translation and protein synthesis. The ribosome-inactivating action leads to “ribotoxic stress”, activation of kinases (SAP/JNKinase, p38) and the induction of apoptosis.
This is also of relevance for triggering apoptosis of cancer cells if Aviscumine is applied close to a solid tumor and – in the case of internalization by antigen-presenting-cells (APCs) – for starting the immune cascade.
The receptor mediated internalization by APCs comes over numerous steps to the generation of membrane vesicles. This provides a large surface for antigen-presentation – an important prerequisite for strong T cell responses. In other words, the membrane vesicles with their antigens act as conveyors of immune response. Aviscumine induces release of cytokines mediating the anti-cancer activity of the immune system and increases the cytotoxic activity of killer cells against tumor cells.
On the basis of the results of phase I and II trials with Aviscumine as well as due to its mode of action it is obvious that Aviscumine should also demonstrate clinical activity in various immunogenic tumor entities beyond melanoma.
Effect on metastases
Aviscumine (ME-503) is active in different tumor cell lines as well as in syngeneic and xenograft animal models.
Especially, the influence of aviscumine on the formation of lung metastases in mice bearing B16-F10 melanoma cells was studied in cooperation with the in this area very experienced Cellvax in Evry (France).
The dose of 3 ng Aviscumine/kg body weight significantly reduced the number of lung metastases compared to untreated animals.
In several clinical trials (> 132 Pts.) using different application routes and dose ranges, Aviscumine has demonstrated good response in solid tumors (control of disease) and a favourable safety profile. A phase-II-trial in 31 patients with Aviscumine has recently demonstrated its effectiveness in patients with advanced metastatic melanoma (Trefzer et al., 2014). The further clinical development is in preparation.