In the ADC development, it is crucial to choose highly potent toxins. Toxins targeting tubulin filaments are adaptable for ADCs and have been widely explored. By leveraging experience in biopharmaceuticals, Creative Biolabs has developed ADC molecules with toxins of this class.
Figure: Effect of auristatins and maytansines on microtubule formation (Biosci Rep, 2015)
There are three major types of proteins forming cytoskeleton, actin filaments, microtubules and intermediate filaments. Intermediate filaments are only found in some metazoans while actin filaments and microtubules are abundant in all eukaryotic cells. Actin filaments are abundant beneath the plasma membrane and play critical roles in cell migrating, engulf particles and dividing.They can provide mechanical support, allow movement of cell surface and determine cell shape. Microtubules are dynamic structures, just as shown in the figure, they undergo continual assembly and disassembly in cells. Microtubules are generally composed of 13 linear protofilaments that are assembled around a hollow core. The structures forming microtubules are tubulin dimer. Tubulin is a type of globular protein and as a dimer, it consists of two related polypeptides, α-tubulin and β-tubulin. γ-tubulin is an additional type of tubulin to initate microtubulin assembly. Microtubules play a central role in mitosis, so drugs affecting microtubules are great candidates in the treatment of cancer. In ADC development, toxic moieties that target tubulin filaments mainly include maytansinoids, auristatins and taxol derivatives. These drugs disrupt microtubule function, blocking cell mitosis and resulting in the death of cells in active division with different mechanism of actions. Maytansinoids and auristatins bind to tubulin and inhibit tubulin assembly. Taxol derivatives function by stabilizing microtubules rather than inhibiting their polymerization, which also blocks cell division. A variety of ADC constructs with these drugs have been prepared and evaluated in clinical trials, among which the lead compounds include brentuximab-MMAE, trastuzumab-DM1, etc. These ADCs contribute to the learning process of ADCs and targeted tumor therapy.