Introduction to Cytotoxic ADC Payloads

Posted by beauty33 on January 2nd, 2021

The element of an ADC that ultimately causes its therapeutic effect is the conjugated cytotoxic agent, which is often referred to as “payload" or “warhead." Several molecule classes have proven successful in ADC context so far and even more with great potential are currently under investigation. Several of the toxins used as ADC payloads today, namely maytansinoids, auristatins, and calicheamicins, have been discovered because of their exceedingly high potency which made them very attractive as possible new anticancer drugs. However, these toxins had an unfavorable TI and the doses required to achieve an anticancer effect came along with serious toxicity, eventually ruling out their further development as standalone anticancer agents. With the advent of ADCs, however, the therapeutic application of these toxins experienced a renaissance. The vast majority of ADCs being developed today carry a cytotoxic payload, but it is worth mentioning that recent approaches also utilize alternative drugs such as immune- stimulatory payloads or antibiotics. In the following section, we will focus on different classes of cytotoxic ADC payloads and have a closer look at the payloads that have reached final success as components of currently approved ADCs.

Maytansine is a macrolide of the ansamycin type that was initially isolated from the bark of the African shrub Maytenus. It is a very potent antimitotic drug that inhibits tubulin polymerization and thereby arrests the cell cycle at the G2/M phase, which ultimately results in cell death by apoptosis. Maytansine and its derivatives, the maytansinoids, showed strong in vitro activity at concentrations in the low picomolar range on different cancer cell lines. The most common dose-limiting toxicities of these compounds are neurotoxicity, vomiting, and nausea. The originally isolated maytansine structure was, however, not very well suited for the covalent attachment to an antibody.

Therefore, derivatives with modifications that allow conjugation to a mAb had to be developed. One of the compounds resulting from these activities is DMI, the payload finally used for trastuzumab emtansine (Kadcyla"). Interestingly, using DM1 as an ADC component increased its maximum tolerated dose (MTD) by at least a factor of two, confirming the concept that incorporation of cytotoxic agents into ADCs improves the TI.

Auristatins are peptide -based molecules and dolastatin 10, the first described agent of this class, has been isolated from the sea slug Dolabella auricularia. Auristatins inhibit the polymerization of microtubules and suppress the tubulin-dependent guanosine-5'-triphos-phate (GTP) hydrolysis. This leads to an interference with mitosis resulting in a cell cycle arrest in the G2/M phase, which finally results in cell death. The most common dose-limiting toxicities of auristatins are peripheral neuropathy (PN), fatigue, nausea, and diarrthea.

Today, mainly two dolastatin 10 analogs, namely monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) are being utilized as ADC payloads.

However, so far only ADCs containing MMAE as active drugs have been approved for therapeutic use, namely brentuximab vedotin (Adcetris'), polatuzumab vedotin-piiq (Polivy"), and enfortumab vedotin-ejfv (Padcev*).

Calicheamicins are enediyne-containing anticancer antibiotics with special structural elements such as a methyl trisulide group and a glycosylated hydroxyl-amino sugar. They were initially isolated from Micromonospora echinospora calichensis and show extraordi-narily high antitumor activity. Calicheamicin γl', for example, showed antitumor activity in murine tumors at doses as low as 0.5-1.5 μg/kg. Calicheamicin makes up the payload in gemtuzumab ozogamicin (Mylotarg ”) and inotuzumab ozogamicin (Besponsa' ) where it is covalently linked to the mAb via an acid-labile linker.

It is a very potent DNA damaging agent and binds to specific regions in the DNA minor grove where it induces double strand breaks finally leading to apoptosis and cell death. The most common dose-limiting toxicities of calicheamicin include thrombocytopenia and neutropenia.

Camptothecin is a pentacyclic quinolone-based alkaloid that was originally isolated from the Asian tree Camptotheca acuminate. It inhibits DNA topoisomerase I, thus effectively stalling DNA replication in the S-phase ultimately resulting in the apoptotic cell death of tumor cells. The initial compound, however, suffered from poor water solubility and the conversion of its lactone into an inactive carboxylate form undercharacteristics of camptothecin have been undertaken. These efforts resulted in the devel-opment of topotecan and irinotecan, which have been approved by the FDA as anticancer drugs. Another important derivative of camptothecin is the substituted exatecan Dxd, which is the payload used for trastuzumab deruxtecan (Enhertu"). The most severe side effects observed during camptothecin treatment include neutropenia and leukopenia.

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