Active Targeting: A New Wave In Drug Delivery

By George Yeh, president, TLC

Although the history of drug development contains many stories of serendipitous discovery, critical advances often emerge by setting out to address specific challenges. Today, many challenges associated with older drugs are being solved with new delivery technologies. These new forms of delivery are capable of guiding a drug directly to the targeted disease tissue or a specific cell type. For many drugs, effectiveness is limited by toxicities resulting from the exposure of healthy, nondiseased tissues to the drug. The expectation for new forms of delivery is that improving old drugs with targeting technology will meaningfully and reproducibly improve therapies across a wide range of disease areas.

THE QUEST FOR THE RIGHT TECHNOLOGY
Developing a targeted therapy requires not only a deep understanding of how this therapy will be applied clinically, but also an understanding of the practical limitations of the technology itself. For example, one type of a targeted drug is an antibody-drug conjugate, where therapeutic molecules are chemically linked to antibodies with specific affinity to a cellular target. While this approach has produced approved drugs, its activity and broad utility in many contexts may be limited by the low ratio of therapeutic payload molecules to the number of antibodies.

One way to address the issue of payload ratio may be through the use of lipid-based nanoparticles, coated with antibody fragments to provide cellular targeting, each containing thousands of drug molecules. Although the hope of this effort and others is to demonstrate an efficient and broadly applicable technology, there may not be a one-size-fits-all approach for targeted delivery. Still, the promise of antibody-based targeting technologies for improving efficacy and reducing toxicity is clear.

CHOOSING THE RIGHT INDICATION
The concept of targeted therapies is particularly compelling in oncology, where dose-limiting toxicities — common consequences of cytotoxic drugs — significantly limit a drug’s therapeutic potential. Other areas where more targeted therapies could benefit from this approach are those where disease biology is mediated by specific cell types, including infectious diseases, brain disease, heart disease, diabetes, or lung-specific drug delivery. In addition to disease biology and side effects of existing treatments, important considerations in determining an indication for development of targeted therapeutics are the costs of treatment and costs of manufacturing. Many drugs using existing targeting technologies are exceedingly costly to manufacture, so a careful analysis of both treatment limitations and costs is required.

ADVANTAGES OF INCREMENTAL ENGINEERING
From a high-level view, narrowly addressing the drug delivery component of a new therapy, such as adding targeting capabilities, has additional advantages. Changes in biodistribution resulting from targeted delivery can be relatively straightforward to assess in preclinical models, thus reducing the risk of unexpected effects during clinical development. In addition, incremental changes to delivery can be evaluated for their effects on known safety risks, which can be more easily avoided early in the development process. Optimizing drug delivery by improving targeting, isolating only that variable in the overall process of drug development, also helps in defining clear clinical benchmarks. This is in part because nontargeted versions of a similar therapy provide an easy point of comparison for an actively targeted therapy.

While there is much work yet to be done in refining targeted drug delivery technologies before advances are reproducibly and broadly demonstrated in the clinic, the promise of the concept justifies current widespread efforts.