ADC Payload

Microtubules are an important part of the cytoskeleton in eukaryotic cells. Tubulin forms microtubules, and tubulin inhibitors interfere with the dynamic assembly of microtubules by binding to tubulin, arresting cells in the G2/M phase of the cell cycle, and ultimately leading to apoptosis. More than half of the ADCs currently in clinical development use tubulin inhibitors (auristatins and maytansinoids) as ADC payloads. The first class consists of microtubule inhibitors that disrupt microtubule assembly and affect mitosis.

Typical payloads include monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), maytansine-like ADC payloads such as DM1, DM3 and DM4, Tubulysins, and polyether macrolides like Eribulin. Contact ChemExpress for tailored services designed to meet the specific needs of your ADC payload program.

Compared to tubulin inhibitors, DNA inhibitors can act on the whole cell cycle by destroying DNA through double-strand breakage, alkylation, chimerism, crosslinking, etc., causing cytotoxic effects and having a good therapeutic effect on solid tumors. In addition, DNA inhibitors have far fewer targets than tubulin inhibitors, and DNA inhibitors can show a better killing effect when ADCs carry the same amount of payloads into the cells. ADCs with DNA inhibitors as payloads can target tumor cells with low antigen expression, which explains why DNA inhibitors have been chosen as payloads in many next-generation ADCs. Other types of drug payloads currently under active clinical development are RNA-modifying drugs (amatoxins), protein toxins, antibiotics, and enzymes.

Representative DNA-damaging payloads include enediyne, topoisomerase I inhibitors, and pyrrolo benzodiazepines (PBD). Topoisomerase I inhibitors include camptothecin- and non-camptothecin-based compounds, represented by Exatecan, SN38, and Deruxtecan (Dxd).

In addition to some of the conventional ADC payloads described above, there are many novel potential ADC payloads, such as topoisomerase II inhibitors, RNA polymerase inhibitors, Bcl-xL inhibitors, and immune stimulants. Additionally, glucocorticoids are now emerging as ADC payloads for indications beyond oncology.

ADC with PROTAC molecules as payloads: Antibody‒PROTAC conjugates combine the catalytic properties of PROTAC with the tissue specificity of ADCs, thereby overcoming the traditional limitations of targeted degraders and ADCs, with great potential for targeting novel targets.

ADC with dual payloads: With the advent of ADC therapy resistance, binding one antibody to two or even more different payloads, Dual-Payload ADCs provides an attractive option for the development of next-generation ADCs.

Payloads of PDC: The PDC payloads can be divided into chemical drugs, protein drugs, and peptide drugs. Chemical drugs represented by DM1, MMAE, KSP inhibitors, camptothecin, doxorubicin, paclitaxel, methotrexate, daunorubicin, and gemcitabine are commonly used. Protein drugs mainly include interferon and tumor necrosis factor. Radioisotopes are also commonly used as payloads for PDCs.