Therapeutic antibody–drug conjugates or ADCs (also known as immunoconjugates) selectively kill tumor cells that overexpress a specific target antigen while limiting drug toxicity to normal, healthy tissues.[1]

With two approved drugs (brentuximab vedotin – Adcetris®; Seattle Genetics and ado-trastuzumab emtansine/T-DM1 – Kadcyla®; Genentech/Roche), and many agents in clinical trials, these novel drugs are becoming an increasingly important class for treatment of cancer and hematological malignancies.[2]

Antibody–drug conjugates are a mixture of antibodies (mAbs) covalently conjugated to varying amounts of cytotoxic (anti-cancer) drugs through either lysine or cysteine residues.

Critical Factors
Among factors critical to the clinical efficacy of antibody–drug conjugates are the target site-specificity and binding properties of the antibody. The in vitro and in vivo stability of both a stable linker and drug species as well as the potency of the cytotoxic drug are also crucial.

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Drug-to-antibody Ratio
Another important quality attribute is distribution and average number of drug species on the antibody. The drug-to-antibody ratio or DAR, is an important quality attribute of an antibody-drug conjugate. DAR significantly affects an antibody–drug conjugate’s safety and efficacy: low drug loading reduces potency while high drug loading can negatively affect pharmacokinetics.

These critical factors emphasize the importance of understanding the physicochemical properties of antibody–drug conjugates as well as selecting the appropriate analytical and bioanalytical techniques during manufacturing and storage.[3]

Characterization Challenge
Although the concept of antibody–drug conjugates may seem quite simple, to successfully develop them is rather complex and depends on the correct selection of each of the components (antibody, linker and cytotoxic drug) as well as the corresponding conjugation chemistry. [4]

Furthermore, the nature of the conjugation chemistry and the complexity and heterogeneity of antibody-drug conjugates (more complex and heterogeneous structures than the corresponding antibodies) presents a challenge to some of the conventional analytical methods scientists have relied upon for biologics characterization.[4] But by using the correct approach, scientists are able to get a proper understanding of an antibody–drug conjugate when conventional analytical techniques can only provide an incomplete picture of antibody–drug conjugate product quality.

An educational video (developed by Waters Inc.) addresses some available solutions designed to characterize Antibody-drug Conjugates.[5]


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