Cytolysin

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

TubulysinaTubulysins

 

 

 

 

 

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

 

Rabbit Lysate HeLa CellsMouse LD50
IC50 (pM) IC50 (pM) (μg/kg)
Ricin 100 0.67 3.00
Nigrin-b 30 27,600.00 12,000.00

 

NIGRIN-B
NIGRIN

 

 

 

 

 

 

 

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