Antibody-drug conjugates (ADCs) have gone through several waves of enthusiasm since being first tested in animal models in the 1960’s. The first clinical trials with ADCs were conducted in the 1980’s, and an ADC was first approved in 2000 (Mylotarg, see below). Mylotarg, however, was famously withdrawn from the market first, before being reintroduced in 2017.
In the 2010’s, the launch of a few clinically and commercially successful blockbusters (e.g. Adcetris) renewed enthusiasm for the ADC modality, bringing in a wave of investment including from non-specialist investors such as Peter Thiel’s Founder’s Fund. Later high-profile trial disappointments of initially promising PDB-dimer-based therapeutics such as Stemcentryx’s SCLC drugs once again spooked the field, stoking uncertainty about whether meaningful therapeutic indexes could be achieved beyond initial successes due to factors like bystander toxicity. Were most ADCs in development just “fancy chemo,” slowly releasing systemic cytotoxins?
With a whopping 8 ADCs approved in the last 4 years, a battery of impressive new clinical data, and acquisitions at stunning valuations such as Gilead’s $21B purchase of Immunomedics, antibody-drug conjugates are back on the front pages of the news. And there’s good reason to be excited about the field. While traditional small-molecule-based ADCs are demonstrating meaningful benefit in notoriously hard-to-treat indications like triple-negative breast cancer, new modalities are also emerging with different classes of payloads such as oligonucleotides, proteins, and degraders. ADCs are being tested in new indications outside of oncology, and new conjugation and antibody engineering technologies are enabling huge diversity in both the targeting element and the warhead.
The field seems to be in another phase of exponential growth, so below is a visual “rest-stop” to catch up on what’s currently approved. The first image contains a list of FDA approved antibody-drug conjugates with their targets and the structures of some representative warheads, and the second infographic contains a list of linker-payloads/warheads used in the FDA approved ADCs. Subscribers can get the high-resolution PDFs of both infographics directly by e-mail and links to helpful reviews about each ADC appear below.
The Resurgence of Antibody-Drug Conjugates – FDA Approved ADCs, Warheads, and Linkers
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List of Approved Antibody-Drug Conjugates and Reviews
- Zylonta (loncastuximab tesirine) – CD19-targeted ADC
- Blenrep (belantamab mafodotin) – BCMA-targeted ADC
- Trodelvy (sacituzumab govitecan) – Trop-2-targeted ADC
- Enhertu (trastuzumab deruxtecan) – HER2-targeted ADC
- Padcev (enfortumab vedotin) – Nectin-4-targeted ADC
- Polivy (polatuzumab vedotin) – CD79-targeted ADC
- Lumoxiti (moxetumomab pasudotox) – CD22-targeted ADC
- Besponsa (inotuzumab ozogamicin) – CD22-targeted ADC
- Kadcyla (trastuzumab emtansine) – HER2-targeted ADC
- Adcetris (brentuximab vedotin) – CD30-targeted ADC
- Mylotarg (gemtuzumab ozogamicin) – CD33-targeted ADC
- Tivdak (tisotumab vedotin) – TF-directed ADC (accelerated approval Sep. 24, 2021)
We hope this is a useful checkpoint for getting caught up with ADCs amidst the whirlwind of exciting new technology. Explore drughunter.com for more drug discovery articles.