Toxins Targeting RNA

Creative Biolabs has established various platforms to develop ADCs. Based on different mechanisms of action, payloads of ADCs can be classified into three categories: anti-mitotic (tubulin filaments damaging), DNA damaging or transcription inhibitors.

Figure: Model of RNA polymerase II transcription initiation machinery (PNAS, 1999)

In mammalian cells, inhibition of DNA transcription leads to apoptosis. RNA polymerase, along with transcription factors, regulates transcription, which is a crucial step in control of cell growth and differentiation. Based on the conception, transcription inhibitors are a novel strategy to develop therapeutic ADCs. In eukaryotes cells, there are three nuclear enzymes, Pol I, II, and III, to yield different classes of RNAs. Pol I is about 590-kilodalton and contains 14 subunits. It transcribes the large ribosomal RNA genes, which initiates ribosome biogenesis and regulates the growth of eukaryotic cells. Pol II is at the center of the transcription machinery and transcribes mRNA, snRNA and regulatory RNA; and Pol III is responsible for some noncoding RNA transcription and regulates cell growth, proliferation and response to stress. These three polymerases initiate transcription with distinct types of promoters but share a common transcription factor TBP (TATA-binding protein). Transcription factors refer to the proteins that contain DNA-binding domains (DBDs) and bind to specific DNA sequence to regulate the rate of transcription. In ADC development, the lead components of transcription inhibitors are amatoxins and they can bind to RNA-polymerase II of eukaryotic cells with the highest affinity found for mammalian enzymes. As known so far, α-amanitin is the most potent and specific inhibitor for the RNA polymerase II, leading to cell apoptosis.

With rich experience in antibody engineering and manufacturing, Creative Biolabs can provide various payloads and appropriate conjugation strategies to assist your ADC research for scientific and clinical purposes.

Categories of ADC payloads that Creative Biolabs provides:

• Toxins targeting tubulin filaments: Maytansinoids, Auristatins, Taxoids, etc.
• Toxins targeting DNA: Calicheamicins, CC-1065 analogs, Duocarmycins, etc.
• Toxins targeting RNA: Amatoxins, etc.
• Nanocarriers
• Protein toxins
• Enzymes

References

1. Gerhard Moldenhauer, et al. Therapeutic potential of amanitin-conjugated anti-epithelial cell adhesion molecule monoclonal antibody against pancreatic carcinoma. J Natl Cancer Inst. 2012 Apr 18; 104(8):622-34.
2. Frank C. P. Holstege and Richard A. Young. Transcriptional regulation: contending with complexity. Proc Natl Acad Sci U S A. 1999 Jan 5; 96(1):2-4.
3. Steven Hahn. Structure and mechanism of the RNA Polymerase II transcription machinery. Nat Struct Mol Biol. 2004 May; 11(5): 394–403.

For research use only. Not intended for any clinical use.