There are mainly three strategies that are used in the field of ADC technology, inhibitors of microtubule assembly, DNA-damaging agents and transcription inhibitors. Amatoxins are a subclass of transcription inhibitors used to develop therapeutic ADCs.

Figure: Location of α-amanitin bound to pol II. (PNAS. 2002)

To inhibit gene transcription is a novel approach in the field of ADC technology. Amatoxins are a representative of these inhibitors. They belong to a family of highly toxic cyclopeptides produced by mushrooms. There are nine naturally occurring amatoxins known so far which share the same skeletal structure, a ring of eight L-configurated amino acids, bridged between a tryptophan and a cysteine residue by a sulfoxide moiety. Among these molecules, α-amanitin and β-amanitin account for ~90 %. Amatoxins can bind to RNA polymerase II, leading to cell apoptosis. RNA polymerase II is located in the center of the transcription machinery which is the most complex one of the three Pol transcription machineries. The Pol II transcription machinery contains a total of about 60 polypeptides. It mediates the transcription of message RNA, some small nuclear RNA and regulatory RNA. Pol II initiates the regulatory factors binding to DNA sequence and the factors related to transcription are recruited to elongating Pol II. Amatoxins bind RNA polymerase II tightly and block the transcription of DNA into precursors of messenger RNA. The generated ADC conjugating β-amanitin to a MUC1-specific antibody has specific cytotoxicity against breast cancer cell line T47D, which is one of the successful examples of amatoxins-based ADCs.
In ADC engineering and development, there are many unparalleled advantages that amatoxins are developed as warheads. Firstly, they have high solubility in aqueous medium to facilitate the coupling reaction. Secondly, there are fewer chances that ADCs of amatoxins will cause an aggregation. Thirdly, they have fewer side effects and can be excreted in urine very quickly. Taken together, ADCs with amatoxins can be evolved as a promising therapeutic strategy.

Categories of ADC payloads that Creative Biolabs provides:

Jan Anderl, et al. Antibody–Drug Conjugate Payloads. Antibody-Drug Conjugates, 2013:63-67.
David A. Bushnell, et al. Structural basis of transcription: α-Amanitin–RNA polymerase II cocrystal at 2.8 Å resolution. Proc Natl Acad Sci U S A. 2002 Feb 5; 99(3):1218-22. 

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