Better Together

Antibody-drug conjugates (ADCs) are constructed by covalently attaching drugs to antibodies, thus combining the specificity of antibodies with the therapeutic effect of cytotoxic drugs. Ideally, this approach confines the drug to the intended site of action, thereby limiting unwanted effects in healthy tissues and facilitating higher relative concentrations of drug at the target tissue. This is a powerful and exciting class of targeted therapy – and it has considerable promise in oncology; to date, two FDA-approved ADCs (Adcetris and Kadcyla) have reached the market, and around 40 ADCs are undergoing clinical evaluation.

ADC technologies are evolving rapidly, resulting in a correspondingly broad range of conjugation and linker technologies, each with their own advantages and limitations. One of the strongest approaches to gain access to next generation ADCs is through antibody engineering, which is technically challenging, but can result in a controlled, homogeneous product, and since homogeneity tends to mean predictability – this is a desirable feature for any drug. But there are alternatives, not least the application of relatively straightforward reaction protocols to modify native antibodies. These techniques have the advantage of simplicity, but may not always modify all the antibody molecules in precisely the same way. This type of quality issue needs to be balanced against the lower costs that are required for their use in ADC production. Moreover, it should also be noted that more homogeneous technologies in the class of native antibody modification are being developed at an astonishing rate.

At the moment, I don’t believe that any one approach has advanced to the point where it could be considered the best/dominant technology; so there is no single, leading platform technology for ADC manufacture. And although the current methods of ADC construction have gone some way to addressing the challenging issues of creating desired homogeneous antibody-drug conjugates, significant hurdles still remain. In particular, our understanding of the optimal combinations and precise interdependencies of particular features of an ADC – and the way in which these modulate its efficacy and pharmacokinetic profile – remains incomplete. Parameters of importance in ADC construction include the location of the drug on the antibody, the drug-to-antibody ratio, and the homogeneity of the ADC population. It is known that these will affect aspects of the product profile (for example, the required dosage, biodistribution, clearance rate, toxicity, and accumulation at the target tissue), but the nature of these links is not understood in great enough detail at present. In my view, much more work is required before we can completely and reliably predict key features of an ADC from the parameters applied in its design and the methods used in its construction.

Right now, it is unclear which site-specific strategies will be ideal for which drug types or drug-to-antibody ratios, or even which ones will best meet the basic requirements of safety, tolerability and low manufacturing cost. Even if we take the view that product homogeneity is an essential requirement, there is still no single technology that can be generally applied for the preparation of engineered, homogeneous ADCs with completely predictable attributes. Therefore, each site-specifically modified ADC must be constructed in a tailor-made fashion, building a method that works for the specific antibody and drug combination in question.

But it’s not all negative – there is good news! I believe that we will gain a much better understanding of the influence and consequences of each site-specific modification strategy over the coming years, which means that the next generation of antibody-based targeted therapy will be based on a more rational design of bioconjugates, such that the “A” and the “D” can be connected with predictable effect. Will a single leading technology emerge? Perhaps – but it may be that particular technologies will turn out to be more suited to certain drug types, particular drug loads or specific antibodies. Regardless of the uncertainties around the optimal linkage strategy, I do know one thing: ADCs have an important role to play in the future of targeted therapeutics.