Although all three components of an ADC — the targeting antibody, the linker molecule and the highly potent payload — are essential to its therapeutic activity, it’s the payload that does the damage. The careful selection of this constituent is, therefore, critical. It needs to be sufficiently potent to have the desired clinical outcome and not so toxic that the side-effect profile is unmanageable.
Of the dozen anticancer ADCs that have already reached the market, seven use a tubulin inhibitor; a similar proportion — 62% — of those in the clinic whose warhead has been disclosed, also work via this mechanism.
Monomethyl auristatin E is by far the most widely used agent and occurs, for example, in Adcetris (brentuximab vedotin from Seagen) and Polivy (politumumab vedotin from Genentech). Many more are in the clinic.
Another class of tubulin inhibitor, the maytansinoids, has also reached the market in ADC form. Of note here is Kadcyla (trastuzumab emtansine, Genentech), which uses the maytansine analogue DM1. This highly potent active pharmaceutical ingredient (HPAPI) includes a thiol group to facilitate linkage to the rest of the ADC. Again, several more are in the clinic.
Three of the remaining five approved ADCs use DNA targeting agents, including Zylonta (loncastuximab tesirine from ADC Therapeutics), whereas the final two involve a topoisomerase I inhibitor, such as Trodelvy (sacituzumab govitecan, Gilead).
The proportions in the disclosed clinical pipeline are similar. Increasing numbers are starting to enter the clinic with alternative payloads, including the immunomodulatory TLR and Sting agonists.
The variety of disclosed payloads in preclinical development is even more diverse, particularly for the tubulin inhibitors. It is notable that interest in ADCs that use immunomodulators is increasing, with numerous biotechs working in the area.
Regardless of its mechanism of action, several factors are important for the HPAPI in an ADC. Its half-life must hit the sweet spot between too long and too short; its bystander killing activity and systemic accumulation must be compatible with clinical use; and there should, ideally, be a low potential for resistance developing. And, of course, cost is always a consideration.
Another key trend is the appearance of ADCs in therapeutic areas other than cancer. None of these are yet on the market, but it is surely only a matter of time. Examples include the programmes to develop antibody–oligonucleotide conjugates at Avidity and Dyne, both of which use siRNA conjugated to antibodies for musculoskeletal conditions.
It is certain that more diverse therapeutic areas and novel payloads will appear in the coming years, with protein degraders, steroids and even kinase inhibitors being investigated.
With ADC payloads predominantly being HPAPIs, the complexity of their manufacture and manipulation means that significant experience and capabilities are required to make and handle them — although only small volumes will ever be required.
And whereas Big Pharma companies dominate the current approvals list for ADCs, many are now being developed by small biotech companies. All the way from preclinical evaluation through the clinic to commercial launch, these businesses are almost entirely reliant on outsourcing partners to produce material.
It is, therefore, critical that they choose an outsourcing partner with the necessary experience — and the required equipment — to make their products. Containment that meets regulatory requirements is essential to protect both the operators within the plant and the wider environment.
Lonza has responded to the trends in the ADC market by expanding its HPAPI capabilities, notably in China, and invested in dedicated equipment for these important products. We believe that as the ADC market expands into new modalities and novel payloads, the need for experienced, skilled outsourcing partners will only grow, and we are doing our best to anticipate what our customers will need in the coming months and years.
