Table 1.

Characteristics, limitations and comparison of 1st, 2nd and 3rd generation ADCs

1st generation ADCs

• Consist of conventional chemotherapeutic drugs linked to target-specific mAbs via non-cleavable linkers

• Insufficient potency of the payload like doxorubicin, methotrexate. IC50 is mostly in 1–6 μM range

• Immunogenic as murine Abs are used

• Systemic loss of the drug as unstable linker such as hydrazone is used

• Shows off-target toxicity due to instability of the ADC

• Aggregation of ADC in plasma

• Examples: BR96-Dox, Mylotarg®, Besponsa®

2nd generation ADCs

• Consist of more potent payloads like auristatins, maytansinoids, calicheamicins etc.

• IC50 of payload is approximately in the range of nM to pM

• Less immunogenic as chimeric/humanized Abs are used

• Consist of comparatively stable linkers, such as the valine-citrulline, thioester to avoid premature release of drug

• Heterogeneous DAR (0–8) with an average of 3–4 due to stochastic coupling strategies

• ADCs have narrow therapeutic index, limited tumor penetration ability

• Shows off-target toxicity

• Development of resistance

• Examples: Adcetris®, Kadcyla®,Polivy®, Padcev®

3rd generation ADCs

• Consist of potent novel payloads with newer mechanism of action and wider dynamic cytotoxicity range

• Made up of fully humanized antibodies

• Designed through site specific conjugation techniques which ensure homogeneous, single isomer of ADC with well-defined DAR and dynamic cytotoxic range

• No aggregation

• Less off-target toxicity and better pharmacokinetic efficiency

• Efficacious in clinical study

• But still success rate is low due to narrow therapeutic margin

• Examples: Enhertu®, Trodelvy®, Other approved ADCs after 2020