History and Development of Antibody Drug Conjugates (ADCs)
Release date：2019/11/22 17:23:04
Antibody-drug conjugates (ADCs) bind to the principle of targeting cancer cells by tumor-specific antibodies and delivering potent cellular toxins to such targeted cancer cells that are covalently coupled to tumor-specific antibodies. The linkage between the antibody and the toxin should only release the toxin when the ADC binds and/or internalizes into the cancer cell.
In 1913, German physicist and scientist Paul Ehrlich pioneered the concept of targeted delivery of toxic agents against microbes or tumor cells.
In the 1990s, the first generation of ADCs was derived from the backbones of murine. However, the linker was unstable in human blood flow because of which the ADCs had a short half-life.
In addition, the concentration of cytotoxic agents (also known as cytotoxic payloads) was minimal.
Only 1-2% of the dose reached the tumor site, which does not provide the desired therapeutic efficacy in humans. Subsequently, clinical trials were discontinued due to the ineffectiveness of these first-generation ADCs.
At about the same time, the FDA-approved ADC for the treatment of acute myeloid leukemia was terminated due to a fatal adverse event because of the instability of the linker, resulting in the premature release of the cytotoxic payload.
ADCs are challenged due to their complex structure and have some limitations, such as low potency of chemotherapy and low antigen selectivity.
A whole chain of factors influences the overall success of ADC development:
1.) It starts with the selection of the right target. Ideally, the target should be expressed only in cancer cells and tissues, but not in healthy cells or tissues or at negligible levels.
2.) The quality of the targeting antibody must meet the highest quality standards and should provide the best "carrier" molecule with good biophysical and functional properties.
3.) The quality of binding of the targeting antibody may have a significant impact on ADC internalization efficiency and/or target cell killing efficiency.
4.) The quality and potency of toxic payloads represent another composite factor for the successful development of potent ADCs.
5.) First, the linker must ensure that the ADC exhibits high stability in the circulation and does not release its payload until it binds to the tumor. Second, the linker must allow the toxin to be efficiently released into the target tumor cell.
6.) The binding site of the payload to the antibody and the amount of toxin coupled to the antibody or toxin also play an important role in achieving optimal safety and efficacy of the ADC. Traditional chemically conjugated ADCs use the classical maleimide linker chemistry used in most clinical-stage ADCs, neither controlling the conjugating sites nor controlling the amount of drug conjugated to each antibody (the so-called drug-to-antibody ratio, DAR). Conjugation stability at different amino acid side chains may vary significantly depending on the chemical microenvironment of the conjugation site. Furthermore, due to the increased hydrophobicity of the payload, the over-conjugated ADCs with high DARs have unfavorable properties, leading to a higher propensity for aggregation and clearance of high DAR ADCs from serum. The faster clearance and/or de-drugging rates of toxins attached to different conjugation sites increase the non-specific or premature release of the toxin payload in the circulation and negatively impacts the safety of the ADC drug.
Despite numerous setbacks encountered while developing ADCs, rapid progress is being made due to technological advancements such as antibody engineering to introduce novel linkers or site-specific conjugation chemistry to improve the outcome of ADCs.
For instance, strategic linker designs with enhanced hydrophilicity can be used in multi-drug resistant tumors to reduce the binding of the payload in ADCs.
Polyethylene Glycol (PEG) is a chemical compound that is composed of ethylene glycol subunits. The following characteristics make PEG a preferable reagent for chemical linkage in ADC:
Increase in Water Solubility: due to the organic backbone of the structure, PEG is known to augment the overall hydrophilicity of molecules it is conjugated to.
Decrease in Aggregation: The increase in hydrophilicity to the ADC prevents the payloads from aggregating to one another.
Decrease in Immunogenicity: highly mobile in solution due to long hydrophilic chains. Long chains create a large exclusion volume in the solution, which can shield the cytotoxin from the host's immune system.
PEG can be developed with a defined length, homo- or hetero- functional groups at the end of its arms, and structured to have specific cleavage sites or branches.
To optimize on PEG's properties, it is crucial that the developer understand how different chemical modifications and reactions impact the structure of the antibody and cytotoxin. Other features of PEG Linkers include cleavable and non-cleavable linkers, which gives the ADC selective release of the cytotoxin from the ADC.
Biochempeg supplies versatile ADC Linkers, including but not limited to: amine reactive, carbonyl reactive, caboxyl and active ester reactive, thiol reactive, branched, and more.