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The bioanalysis of antibody-drug conjugates (ADCs) is essential for understanding pharmaceutical drug safety and efficiency.
FREMONT, CA: Bioanalysis of antibody-drug conjugates (ADCs) is essential for evaluating the safety and efficacy of this rapidly increasing class of pharmaceuticals. Here are some of the reasons that make ADC bioanalysis so complicated. ADCs are made up of cytotoxic small molecule drugs that have been chemically linked to an antibody. The antibody recognizes a tumor-associated antigen that is only expressed in a limited number of normal cells.
Cleavable chemical linkers are developed to remain stable in the circulation and release the cytotoxic drug (also known as the "payload") when some aspects inside the target cell are triggered. A refined pH range, high glutathione concentrations, or proteolytic cleavage are examples of "releasing" triggers. The resulting free drug will destroy the target cell directly and then leave the cell, causing "bystander killing" of nearby cells.
Non-cleavable linkers, on the other hand, lack an apparent proteolytic cleavage site, allowing the cytotoxic payload to remain inside the cell. ADCs with non-cleavable linkers activate the cytotoxic payload rather than the linker when the antibody is degraded.
ADCs are made up of several different components.
In some cases, the cytotoxic drug may efflux from the cell and be metabolized into smaller segments with other anticancer activity to the parent drug. In general, intact ADCs, free drug molecules, conjugated antibody, and complete antibody are all measured in ADC bioanalysis. This diverse group of organisms poses unique bioanalytical challenges, necessitating identifying techniques appropriate for various stages of research and development.
ADC components are heterogenous
One of the critical causes of variability is the number of drugs attached to every antibody. The drug-to-antibody ratio (DAR), described as the average number of drugs conjugated to each antibody (usually between 0 and 8), influences stability, antigen binding, and, eventually, ADC potency. A lower DAR can minimize ADC potency, whereas a high drug loading can boost clearance, increase the risk of accumulation, and cause the toxic payload to be released prematurely into the circulation.
The conjugation area at which the payload is conjugated to the antibody is another source of heterogeneity. In the meantime, efforts are being made to generate more homogeneous ADCs by monitoring the site and number of drugs conjugated to the antibody, but analytical procedures must account for this variability.