Over the past 20 years there have been eleven FDA approved Antibody-Drug Conjugates (ADCs). ADCs are composed of a drug linked to an antibody (mAbs) that is designed to release their payload at a specifically targeted cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells.
The evolution of ADCs is based on four factors, as outlined in Figure 1. The source of antibody, the chemistry of the linkers, how the linker attaches to the antibody, and what type of drug is used.
The History of ADC Drugs Development can be traced back to the first ADC clinical trial in 1983. Then in 2000 the first-generation ADC, Pfizer's Mylotarg was approved for CD33-positive acute myeloid leukaemia (AML) patients aged over 60. Unfortunately, Mylotarg was removed from the market in 2010 due to the use of non-human antibodies led to an immune response and limited its efficacy.
Several issues with first-generation design were identified, such as low concentration in the plasma, immune response to the animal antibody, linker stability in the blook stream, limited expression of the target antigen, limited internalization, and an optimization of the number of drugs linked to each antibody.
In 2011, several second-generation drugs were approved. Among these were Adcetris (brentuximab vedotin) and Kadcyla (trastuzumab emtansine).
Adcetris (brentuximab vedotin) was designed with a cleavable valine-citrulline linker designed to remain stable in the blood stream and encourage an effective bystander effect that means the drug can kill both CD30 positive and CD30 negative tumors.
Kadcyla (trastuzumab emtansine) combines mAB trastuzumab and chemotherapy emtansine. It relies on an optimized non-cleavable linker, which means that it has a lower toxicity profile, but no bystander effect.
The second-generation designs provided some important insight into how ADCs could be optimized.
Due to limited antigen expression and deliverable amount of ADC available in tumors, DNA alkylating agents and tubulin polymerization inhibitors with sub nanomolar activities proved to be useful when used in combination with other therapies due to high cytotoxicity and narrow therapeutic window.
Cleavable vs. Non-Cleavable Linkers in Antibody-Drug Conjugates were studied, with cleavable linkers shown to have a broader efficacy than non-cleavable ones due to what is call the "bystander effect". This bystander effect occurs when the link is cleaved in the extracellular media outside a tumor and drug subsequently permeates a nearby cell to reach its target.
Choosing the correct site for conjugation on the antibody is important since it can affect potency, stability, and PK properties of the ADC.
Finally, targeting tumors with high level of homogeneity expression inside a tumor and selective expression for tumor tissues is critical when developing a new ADC.
In 2019 the FDA approved three new ADCs; Roche's Polivy (polatuzumab vedotin-piiq), Seattle Genetics and Astellas' Padcev (enfortumab vedotin) and AstraZeneca and Daiichi Sankyo Enhertu (trastuzumab deruxtecan), as third generation drugs.
Both Roche's Policy and Astellas/Seattle Genetics' Padcev rely on the optimised cleavable linker developed for Seattle Genetics' Adcentris. While AstraZeneca/Daiichi Sankyo's Enhertu rely on tetrapeptide-based linker, which aims to break down enzymes present in tumor cells. Enhertu was also optimized to allow it to carry large amounts of cytotoxic payload while remaining tolerable to patients.
In April 2020, Trodelvy (sacituzumab govitecan) was approved by the FDA for triple negative breast cancer (TNBC). Trodelvy targets Trop-2, which is over-expressed on TNBC, to deliver the cytotoxic payload SN-38 to tumors. This ADC uses a hydrolysable linker, which creates an effective bystander effect in the tumor micro-environment.
A notable change in the third-generation ADCs is a narrower drug antibody ratio (DAR). The second-generation drugs would have a DAR of 3-8. The third-generation ADCs have a lower DAR (2-4) that improving drug stability, pharmacokinetics, increase binding and drugs activity to cells with lower antigen levels.
Two of the latest ADCs to be approved, Trodelvy and Zynlonta, were developed with PEG chains as part of their linker technology to improve solubility and stability in vivo.
For more information on how the three different generations of ADCs were developed, please refer to the articles ADC Technology Review in 2021 and ADC Approval up to 2021.
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