Antibody-Drug Conjugates (ADCs) are a class of targeted drugs composed of a drug linked to an mAbs (antibody) that is designed to specifically release their payload at a tumor.
This article will focus on the technological developments that have occurred within the last 20 years of FDA approved ADCs. These developments will focus on the four basic components of ADCs, the antibody, attachment site, linker, and payload as shown in Figure 1.
The antibody, or mAbs, is made by cloning a unique white blood cell. These typically bind only to the same epitope, which is the part of an antigen (Ag) that is recognized by the antibody. After the development of Mylotarg, it was observed that animal antibodies would induce an immune response. This led to the use of chimeric (created through the joining of two or more genes) or humanized (protein sequences have been modified) antibodies.
The most recent ADCs to come on the market have also shown the value of targeting tumors with a selective and high level of homogeneity. The cell surface antigens need to undergo efficient internalization and possess high penetrance, a characteristic whereby a large percentage of tumor samples test positive for the presence of the antigen. Choosing the right antibody should have minimal cross-reactivity with healthy tissues, sub-nanomolar affinity to the target antigen, and a long pharmacokinetic half-life combined with minimal immunogenicity.
Choosing the correct site for conjugation on the antibody is important since it can affect potency, stability, and PK properties of the ADC. As understanding of ADCs design has grown the number and type of attachment sites on mAbs have changed. Initially, the connections were made using lysine amine and then later thiol linkages were targeted at disulphide bonding sites. Now site-specific attachments on engineered antibodies are used fast and highly efficient conjugation.
The drug antibody ratio (DAR) is also important, since the number of linkages an mAbs has impacts both its functionality as well as the deliverable payload. Some ADCs, like Inotuzumab ozogamicin (Besponsa) and trastuzumab deruxtecan (Enhertu), would have a DAR of 6-8. However, more recent ADCs have a lower DAR of 2-4 that improving drug stability, pharmacokinetics, increase binding and drugs activity to cells with lower antigen levels.
After the development of Mylotarg, focus was placed on understanding how to select linkers based on stability of the ADC in the bloodstream and within the cell. Additionally, a linker may be chosen for its solubility, low toxicity, or low immunogenicity. The current ADC drugs on the market have linkers that are often divided into two design groups: cleavable or non-cleavable. Cleavable linkers are designed to be stable in the bloodstream and then release the payload once in the cell. The non-cleavable linkers, such as SMCC, rely on lysosomal degradation within the cell to release the drug payload.
The payload molecule should be selected based on its ability to maintain its function when coupled to the linker, avoid immunogenicity, not affect the internalization rate of the monoclonal antibody, remains stable in low pH, and have a sub-nanomolar potency. As ADC development progressed through the 2010's it has been found that 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.
As new ADCs enter clinical trials it is apparent that even more development on the linker technology will be coming soon. Specifically, the fine tuning of the linkers for stability, solubility, and cleavability.
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