ADC History

Antibody–drug conjugates (ADCs) grew from a century‑old “magic bullet” idea into a major oncology modality in just a few decades.

Concept origins

The intellectual origin is Paul Ehrlich’s early‑1900s “magic bullet” concept: a compound that selectively targets diseased cells while sparing healthy tissue.
By the late 1950s, the first experimental antibody–drug conjugate was reported (antibody–methotrexate for leukemia), and in 1983 the first human ADC trial tested an anti‑CEA antibody–vindesine conjugate in advanced cancer patients.

First-generation ADCs (roughly 1990s–2010)

Early ADCs used chimeric/humanized antibodies, relatively unstable linkers, and DNA‑damaging payloads like calicheamicin or doxorubicin.
The landmark first approval was gemtuzumab ozogamicin (Mylotarg), a CD33–calicheamicin ADC with an acid‑labile hydrazone linker, approved by FDA in 2000 for AML but withdrawn in 2010 due to high toxicity and lack of clear survival benefit, then re‑approved in 2017 at a lower dose and different schedule.

Key features of this first generation: murine or chimeric antibodies, non‑specific lysine conjugation (heterogeneous DAR), acid‑labile linkers, and DNA‑disrupting payloads, providing proof of concept but with narrow therapeutic windows.

Second-generation ADCs (2010s)

Technological advances in humanized antibodies, more stable linkers, and more potent microtubule‑targeting payloads produced the modern “second‑gen” wave.

  • Brentuximab vedotin (Adcetris, 2011): CD30–MMAE with a protease‑cleavable Val‑Cit linker, marking a shift to interchain cysteine conjugation and tubulin inhibitors; it showed much better efficacy and tolerability than first‑gen constructs.

  • Trastuzumab emtansine (Kadcyla, 2013): HER2–DM1 with a non‑cleavable thioether linker via lysine conjugation, demonstrating that ADCs could become standard of care in solid tumors (HER2‑positive metastatic breast cancer).

Second‑generation ADCs used more potent payloads (MMAE, DM1), more stable linkers (protease‑cleavable or non‑cleavable thioethers), and better antibodies, improving efficacy and safety versus first‑gen agents while still relying largely on random lysine/cysteine conjugation and heterogeneous DAR.

Third-generation ADCs (late 2010s–early 2020s)

The next wave introduced topoisomerase I payloads, more sophisticated cleavable linkers, and better control of DAR, achieving wider therapeutic windows and strong bystander effects.

Representative third‑generation ADCs include:

  • Polatuzumab vedotin (Polivy, 2019): CD79b–MMAE, optimized for stability and lymphoma efficacy.

  • Enfortumab vedotin (Padcev, 2019): Nectin‑4–MMAE with strong activity in urothelial cancer.

  • Trastuzumab deruxtecan (Enhertu, 2019): HER2–DXd topo‑I payload with a hydrophilic, cleavable peptide linker and DAR 8, delivering potent bystander killing and redefining HER2‑positive and HER2‑low breast cancer treatment.

  • Sacituzumab govitecan (Trodelvy, 2020): TROP2–SN‑38 topo‑I payload with a cleavable linker, extending ADCs into TROP2‑positive solid tumors.

Third‑generation ADCs are characterized by human/engineered antibodies, enzyme‑cleavable self‑immolative linkers, ultra‑potent payloads (PBD dimers, topo‑I inhibitors), and, increasingly, site‑specific conjugation with more homogeneous DAR (often 2 or 4, though some topo‑I ADCs remain high‑DAR), leading to better PK and less off‑target toxicity.

Toward “fourth-generation” / next-gen ADCs (2020s–)

Recent reviews describe an emerging “fourth generation” focused on data‑driven design, site‑specific conjugation, and integration with immune mechanisms.
Key trends include:

  • Site‑specific conjugation (THIOMAB, enzymatic, glycan‑based) to produce homogeneous ADCs with defined DAR and improved stability.

  • Hydrophilic and conditionally cleavable linkers (PEG or polysarcosine masking, phosphoramidate self‑immolative systems) that enable stable DAR 6–8 constructs with better PK and controlled payload release.

  • Payload diversification beyond tubulin/DNA agents into topoisomerase I inhibitors, immunostimulatory payloads (ISACs), and degraders (DACs), plus dual‑payload and bispecific ADC architectures to overcome resistance.

In short, ADC history runs from Ehrlich’s early “magic bullet” concept and crude first‑gen constructs like Mylotarg, through second‑gen microtubule‑inhibitor ADCs such as Adcetris and Kadcyla, to today’s high‑DAR, hydrophilic‑linker, topo‑I–based ADCs like Enhertu and Trodelvy—and is now moving into a fourth era of site‑specific, multi‑payload, and immune‑integrated designs.

Reviews:

(1) Dumontet, C., Reichert, J. M., Senter, P. D., Lambert, J. M., & Beck, A. (2023). Antibody–drug conjugates come of age in oncology. In Nature Reviews Drug Discovery (Vol. 22, Issue 8, pp. 641–661). Nature Research. https://doi.org/10.1038/s41573-023-00709-2