Citolisina

Three novel cytolysin molecules were designed and synthesized, to be conjugated to Oncomatryx human mAbs in a novel precision drug.

High microtubule polymerization inhibition and cytotoxic activity of the novel cytolysins were confirmed.

Natural Tubulysins:

• Isolated from Myxobacteria
• Very strong cytotoxic activity (nM to pM range)
• Tubulin polymerization inhibitors that block formation of mitotic spindles
• Stable in lysosome enriched cell fraction

Synthetic Cytolysins

• Synthetic Tetrapeptidic analogues of the natural class Tubulysins
• Low MW: 780 g/mol
• Not a substrate of Multiple Drug Resistance proteins
• Highly cytotoxic
• Anti-angiogenic
• Easy-to-conjugate
• Derivatives accesible by total synthesis in sufficient amount for preclinical and clinical development
• Functional group for linker technology can be modified
• Several linker technologies applicable
• Robust IP position

Nigrin b – A chain

 Nigrin b

• Plant toxin from Sambucus nigra (bark)
• Member of Type 2 RIP family
• Heterodimer derived from a unique precursor through post-translational processing
• B chain function: Binding to cell membrane carbohydrates and internalization
• A chain function: 28S rRNA N-glycosidase activity that inhibits E2F binding to ribosome
• Similar RIP activity as Ricin in cell-free extracts
• Much lower Toxicity than Ricin to intact cells and animals
• Different Intracellular Pathway after internalization
• Different surface receptors

recNigrin b – A chain

• Oncomatryx has cloned, expressed in bacteria and purified the recombinant A chain of Nigrin b, responsible for the RIP activity of this plant toxin
• recNigrin b- A chain lacks B chain, the lectin domain that is responsible for the cell internalization and immunogenicity of this toxin
• RIP activity of recNigrin b- A chain is maintained.
• Immunogenicity of recNigrin b- A chain is much lower than Nigrin b, whose immunogenicity is already much lower than other RIPs (Lavelle)
• In silico – predicted immunogenicity of recNigrin b-Achain is lower than commercial therapeutic antibodies as Rituximab
• Robust IP position