Mitigating Aggregation and Immunogenicity in ADC with PEG

adc peg linker

Antibody Drug Conjugates (ADC) are a therapeutic application for cancer treatment.   ADC’s are composed of a monoclonal antibody (mAb) conjugated to a potent cytotoxic agent. High specificity of the monoclonal antibody allows for targeting of tumor-associated cells that contain biomarkers that are not found in healthy cells. Upon reaching the target location, the cytotoxin can induce cell death.

This bioconjugate technique has found its success into the market through ADCETRIS and Kadcyla. These drugs target receptors CD30+ and HER2+, respectively, to eliminate tumor cells.

Although there is an increase of drugs in clinical trials that use this technique, there are still many challenges that can limit applications. One of those challenges is antibody aggregation. Antibody aggregation can be influenced by a multitude of factors, both intrinsic (antibody structure) and extrinsic (environmental).  The cause of these aggregates can be challenging to identify due to the immense amount of variations between each individual ADC complex. Careful design of your ADC is pivotal to decrease the probability of antibody aggregation. The chemical linkage between the antibody and drug plays an integral role in bioconjugation design.

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 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.

BroadPharm supplies versatile ADC Linkers, including but not limtied to: amine reactive, carbonyl reactive, caboxyl and active ester reactive, thiol reactive, branched, and more. See our listing below: