Hitting the Spot

In an ideal world, when a person takes any medicine, the active ingredients would go right to the specified part of the body they’re meant to treat. But that’s not how it works. We often need to distribute medicines throughout the body in order to hit our desired targets. This means higher doses and potentially greater side effects. It also limits our ability to deliver medicines that are prone to disintegrate before reaching their target.

These challenges are why we and others have worked to develop a class of medicines called antibody-drug conjugates (ADCs). In the past two decades, four ADCs have been approved by the U.S. Food and Drug Administration for the treatment of certain blood cancers and one for a specific type of breast cancer.

In cancer and beyond, the potential of this technology continues to grow as researchers devise better ways to construct ADCs.

“For most new drugs, we have some framework for how to connect to an antibody without destroying their ability to do their job,” says Tom Pillow, PhD, Senior Scientist in Discovery Chemistry.

These technology advancements mean that a new generation of ADCs has the potential to deliver a broader range of medicines, including targeted cancer therapies and treatments for infections and other types of diseases. Along with other innovative approaches based on genomics and immunology, ADCs have the potential to increase the precision of cancer treatment and give patients more options.

Step Ahead

As a part of our multi-pronged strategy to develop new cancer therapies, we were an early adopter of ADCs. With years of experience in designing antibodies to target specific cancer cells, we combined our internal expertise with technology from our external partners to take the next step of joining antibodies with chemotherapy medicines. ADCs have the advantage of delivering toxic chemotherapy compounds directly to cancer cells, turning it into a much more precise treatment.

“Blood cancers in particular were a natural place to focus. The numerous cell-surface targets meant we could pick the best one for a given type of cancer,” says Andy Polson, PhD, Principal Scientist in Translational Oncology.

Now, he and his colleagues are thinking about how to broaden the reach of the technology, by combining antibodies with different kinds of cancer therapies and with medicines for other diseases as well. With the lessons they’ve learned by developing ADCs for blood and breast cancers, they’re ready to think more broadly about any area where delivering a medicine directly to a particular cell type could boost its efficacy, reduce its toxicity, or both.

Precision Chemotherapy

ADCs arose from a fairly simple idea: What if you could design a linker molecule to join an antibody to a chemotherapy compound? Antibodies recognize certain unique proteins on a cell’s surface and bind them, then get absorbed into the cell along with whatever they may be bound to. With the right design, once a cell absorbed an entire ADC complex, the linker molecule would degrade and the chemotherapy would kill the cell.

Such a strategy is especially beneficial for cancer treatment, because standard chemotherapy targets all fast-growing cells including healthy ones—and causes many potential side effects. While ADCs do still cause some side effects, scientists hoped to mitigate some of the toxicity seen with chemotherapy by delivering it directly to cancer cells. ADC therapy could also potentially use chemotherapy medicines that are normally too toxic to deliver throughout the body, providing a more efficient approach.

The strategy behind ADCs was clear, but the process to engineer a stable linker that fit perfectly with an antibody and its partner medicine, as well as refining the dosage, proved very challenging.

Hold On

Over the years, our scientists have developed novel linker technologies that can be used interchangeably with different antibody-medicine combinations.

“Essentially, we’ve built an adaptable system that allows us to mix and match antibodies and linkers to develop the most stable and effective drug possible,” says Pete Dragovich, PhD, Staff Scientist in Discovery Chemistry.

Our scientists have also pioneered a strategy to improve the consistency of ADCs. Originally the chemical processes used to develop these medicines resulted in molecules with a varying number of drug molecules per antibody. While still effective for treating patients, these methods can cause inconsistent side effects, limiting the dose of medicine a patient can receive. To solve this problem, Genentech developed THIOMAB™ antibody technology, which uses protein chemistry to link a specific number of drug molecules with each antibody.

“Our system allows us to adapt the molecular specifics of the ADC, including its delivery mechanism, based on the target cells we are going after,” adds Doug Leipold, MS, Staff Scientific Researcher in Development Sciences. “This adaptability enhances our ability to specifically target ADCs where we want them to go.”

Potent Combination

“There was no way for any one department to have accomplished this project in isolation,” Andy says. “Collaboration across teams from preclinical to clinical development to manufacturing was the key to refining ADC technology.”

To create the next iteration of ADC engineering, our researchers are now working on ways to boost the potency of the treatment by increasing the drug-to-antibody ratio. Linking more drug molecules to each antibody has the potential to increase treatment efficiency for patients by reducing the dose that needs to be administered. Additionally, this approach can increase the potency or efficacy of a milder medicine by delivering a higher dose.

Researchers are also investigating how to expand the breadth of what ADCs can deliver to include targeted cancer therapies or DNA-based molecules. Our scientists have already demonstrated how versatile ADCs are by conducting proof-of-concept experiments to show the potential of these medicines to treat serious bacterial infections. Moving forward, they hope to explore the potential of ADCs in immunological disorders, many of which also involve cellular targets with abundant surface proteins for ADCs to seek out.

“We’ve developed the infrastructure now to take just about any payload and link it stably and reversibly to the antibody, which is one of our goals with an ADC,” says Tom. “As the technology expands in cancer treatment and beyond, we want to utilize the breadth of expertise and resources at Genentech to identify the drugs that will be most beneficial for patients.”