Since they were originally explored in animal models in the 1960s, antibody-drug conjugates (ADCs) have seen many booms. The initial ADC clinical studies took place in the 1980s, and Mylotarg, the first ADC drug, was approved in 2000. The removal of Mylotarg, however, came as a huge shock to the industry, and it was relaunched in 2017. The launch of a number of clinically and commercially effective drugs (e.g. Adcetris) in the 2010s reignited interest in the ADC model, resulting in a surge of investment. Later, clinical trials of highly anticipated PDB dimer therapies (e.g., Stemcentryx’s SCLC medication) failed due to bystander toxicity and other issues, causing the field to panic once more, sparking a debate on whether significant therapeutic metrics could be acquired beyond early success. As many as eight ADCs have been approved in the last four years. An impressive array of new clinical data and stunning valuation acquisitions such as Gilead’s $21 billion acquisition of Immunomedics have brought ADC drugs back into the limelight. Traditional small molecule-based ADCs are showing meaningful advantages in difficult-to-treat indications such as triple-negative breast cancer, and new drug design paradigms are emerging, such as new payload classes including oligonucleotides, proteins, and degradates. ADCs are being tested in new indications outside of oncology, and new linker and antibody engineering technologies are enabling targeting components and warheads with great versatility. The field appears to be in another phase of exponential growth. FDA-approved ADC drugs, their targets, and the structures of some representative warheads (from Drughunter)Zynlonta | CD19(loncastuximab tesirine-lpyl)PBD dimer (SG3199) – cleavable linkerlarge B-cell lymphoma0.15 mpk IV Q3W 2 cycles to 0.075 mpk Q3WADC Therapeutics (2021) Blenrep | BCMA(belantamab mafodotin-blmf)MMAF – non-cleavable linkerrelapsed or refractory multiple myeloma2.5 mg/kg IV over 30 min, Q3WGlaxoSmithKline (2020) Trodelvy | Trop-2(sacituzumab govitecan)topoisomerase I inhibitor (SN38) – cleavablemetastatic triple-negative breast cancer10 mg/kg IV on d1, d8 – 21d cycleImmunomedics (acq. Gilead) (2020) Enhertu | HER2(trastuzumab deruxtecan)topoisomerase I inh. (deruxtecan) – cleavableunresectable or metastatic HER2+ BC5.4 mg/kg IV over 90 min, then 30 min, Q3WAstraZeneca/Daiichi Sankyo (2019) Padcev | Nectin-4(enfortumab vedotin)monomethyl auristatin E, cleavable linkeradvanced or metastatic urothelial cancer1.25 mpk IV over 30m Q1W, 3 wk of 28d cycleAstellas/Seattle Genetics (2019) Polivy | CD79(polatuzumab vedotin-piiq)monomethyl auristatin E, cleavable linkerRR diffuse large B-cell lymphoma1.8 mg/kg IV Q3W for 6 cyclesGenentech, Roche (2019) Lumoxiti | CD22(moxetumomab pasudotox)Pseudomonas exotoxin, cleavable linkerrelapsed or refractory hairy cell leukemia0.04 mpk IV over 30m, d1, 3, 5 of 28d cycle, 6xAstraZeneca (2018) Besponsa | CD22(inotuzumab ozogamicin)calicheamycin, cleavable linkerRR CD22+ B-cell precursor ALL1.8 mpm2 IV Q1W 21d cycle, Q1W 3 wk/28dPfizer/Wyeth (2017) Kadcyla | HER2(trastuzumab emtansine)maytansinoid (DM1), non-cleavable linkerHER2-positive metastatic breast cancer3.6 mg/kg IV over 90m, then 30m Q3WGenentech, Roche (2013) Adcetris | CD30(brentuximab vedotin)monomethyl auristatin E, cleavable linkerreplased HL and relapsed sALCL1.8 mg/kg IV over 30 mins Q3WSeattle Genetics, Millennium/Takeda (2011) Mylotarg | CD33(gemtuzumab ozogamicin)calicheamycin, cleavable linkerrelapsed acute myelogenous leukemia3 mg/m2 IV on days 1, 4, & 7Pfizer/Wyeth (2000/2017) Legend | Ab Targetnon-proprietary namewarheadindicationadministrationsponsor and/or originator (year approved)