Special Delivery: Precision Targeting of Molecular Therapeutics
Almost every drug has some sort of toxicity. Even over-the-counter drugs like acetaminophen and aspirin can cause dangerous side effects with high doses. “In many cases the side effect comes not from the drug hitting the cells that need treatment, but from the drug hitting cells somewhere else,” says Bryan Laffitte, Director of Discovery Pharmacology at the Genomics Institute of the Novartis Research Foundation (GNF). “If you can target the drug towards the cells of interest and away from others, you can potentially limit side effects.”
This is the goal of a key initiative at GNF. We aim to deliver drugs precisely where they are needed using molecular targeting. Most drugs are already targeted, meaning that they act on a specific cellular process in a diseased cell. But often, that cellular process happens elsewhere, too. For instance, a drug may target fast-dividing cells to treat cancer, but also cause hair loss because hair follicle cells are also fast dividing.
Molecular targeting combines the drug with another molecule that seeks out a more precise cellular address. “The idea is to have a drug that does not do anything before it gets to the site of action,” says Valentina Molteni, Director of Medicinal Chemistry at GNF and co-leader of the initiative with Laffitte.
We’re interested in applying this approach to diseases such as cancer because it provides a way to safely deliver high doses of toxic drugs into tumors with the potential to provide more robust responses. But we also plan to apply it to chronic diseases, for which patients need therapies they can take indefinitely without compromising their quality of life.
The idea of molecular targeting is not new. Antibody-drug conjugates do exactly this, in some cases delivering extremely toxic drugs directly into tumor cells. But at GNF we are using new methods of targeting, such as employing small molecules that recognize specific cellular addresses or prodrugs that become active only in the presence of cell-specific enzymes. A benefit of these approaches is that molecularly-targeted drugs can be taken orally, in pill form, while drugs involving antibodies must be injected.
The idea is to make molecular targeting a widely applicable strategy by developing methods for doing it on a regular basis.
One challenge is discovering cellular addresses specific enough to reduce side effects. To find them, we are leveraging our skills in high-throughput screening, protein science, and small molecule chemistry, along with our expertise in a range of diseases. We are also devising new ways to discover cellular addresses and pairing them with therapeutics more systematically. “The idea is to make molecular targeting a widely applicable strategy by developing methods for doing it on a regular basis,” says Laffitte.
At GNF, we have already identified a list of promising applications of molecular targeting for oncology, diabetes, and inflammatory diseases.
This initiative is allowing us to consider resurrecting drugs that have already proved effective against disease but ultimately failed because they were too toxic for use in humans. By guiding these drugs to the cells that need them most, one could reduce problematic side effects. “These drugs already have a well-defined toxicity profile, so we can clearly see if there is improvement with molecular targeting techniques,” says Molteni. “Our goal is to open the safety window.”
The approach also allows us to cast a wider net in efforts to discover novel therapeutics because we can now consider drugs that target common cellular processes. In the past, we would have ruled out such therapeutics for having too broad an effect on healthy tissues.
Molecularly-targeted drugs come with all of the challenges of traditional drugs, and then some, because these drugs interact with more than one cellular process. “It’s complicated, but we have a very interdisciplinary setup here to meet the challenge,” says Molteni. “It’s worth the effort because there are a lot of benefits to going directly to the cell where the disease is.”