ADC Generation X or is that Generation Xth

I was reminded this week that we are celebrating the 10^th anniversary of the approval of Adcetris®, a pioneering ADC that gave the field a much needed boost after the voluntary withdrawal the year earlier from the only previously approved ADC, Mylotarg®.

Adcetris® was based on a next-generation linker-payload technology vedotin and was many years in the making, but I found myself thinking – what does “next-generation” ADC mean? It has been used for a long time now to describe the ongoing development iterations of ADCs, but aren’t we always in that “next-generation” phase? What exactly are the different ADC generations?

Damelin notes in his ADC book that “next generation is a significant advance that reflects a new capability or approach”. So what generation of ADC are we on now?

The seminal Nature Reviews article by Alain Beck in 2017 nicely attempted to group ADCs in terms of their generational development. According to Beck, a 1^st generation ADC was gemtuzumab ozogamicin (Mylotarg®) characterised by a high portion of unconjugated antibody, poor CMC characteristics and high toxicity with a therapeutic index (TI) on a par with traditional chemotherapies. 2^nd generation ADCs were brentuximab vedotin (Adcetris®) and trastuzumab emtansine (Kadcyla®) that had better CMC characteristics with reduced amounts of unconjugated antibody but still had a narrow TI. 3^rd generation ADCs have site-specific conjugation technologies, no unconjugated antibody, improved stability and pharmacokinetics and a wider TI, exemplified by vadastuximb talirine or IMGN779.

However according to Vankemmelbeke, 1^st generation ADCs used conventional chemotherapy cytotoxins but were hindered by the lack of toxin potency; 2^nd generation ADCs used increased potency auristatin, maytansinoid or calicheamicin cytotoxins, but retained heterogeneity and narrow therapeutic window; 3^rd generation ADCs are site-specific, have homogeneous toxin loading, and use novel mechanism payloads.

Whichever way you label things, overall the generation of ADCs has been characterised by increasing payload potency, a homogeneous drug-antibody ratio (DAR), and a widening of the TI.

You could make a case for some of the more recent higher DAR “next generation” ADCs developed by Daiichi Sankyo (Enhertu®) and Immunomedics (Trodelvy®) being 3^rd generation, but is this the end of the generation game? Ulf Grawunder from NBE Therapeutics and Philipp Spycher from Araris Biotech both make compelling cases for their ADC technologies being classed as 4^th generation, but this raises the important question over what this means for other technology platforms offering improvements including Ambryx, Byondis, Catalent, Synaffix, Abzena, Sutro Biopharma or Ajinomoto? Do these also fit into the 4^th generation ADC iteration? And if there are linkers that incorporate non-cytotoxic payloads such as oligonucleotides, immunomodulators, or check-point inhibitors, are these 5^th generation ADCs or 5^th generation ADC linkers in 3^rd or 4^th generation ADCs?

I’m starting to see that it’s not a bad thing to always being in the “next-generation” ADC phase.

We have seen that members of Generation X truly adding to the development improvements in the ADC field, but perhaps now we are starting to see Millennials up their generation game and now next-generation ADCs are reflected by the new capabilities and approaches.

#ADC