On-and-Off Switches for More Precise Medicines Against Cancer
Protein engineering is allowing researchers to program antibodies so they turn on and off in certain conditions to more precisely target tumors.
Conditional Activation is All Around Us
Our daily lives are built around conditional activation – doing something only when certain conditions are met.
I will take you to the movies, if you clean your room.
We will go on vacation, if the airfares drop.
Stop at the red light, and go once it turns green.
In human biology, conditional activation is also possible. Like software engineers who write code based on if/then statements, researchers are uncovering ways to program antibodies with instructions telling them when to activate, and to do so only in specific circumstances. For example, taking advantage of what is already present in the body’s own environment where the goal is to more precisely target diseased tissue, such as tumors and spare normal, healthy tissue.
“The idea of conditionally activating drugs is a fundamentally next-generation concept in drug discovery and development because traditionally, most drugs have been active systemically throughout the body,” says Andy Goodearl, Ph.D., director of biologics discovery, AbbVie. “By programming antibodies with what amounts to an on-and-off switch so they know where to work and where not to work, not only can we go after diseased tissue with precision, but also we open up a wide range of potential targets once thought to be untouchable because of their widespread prevalence in cells throughout the body.”
The Masked Antibody
Multiple approaches utilize the proteases found around the tumor microenvironment or other diseased tissue. Proteases are enzymes that break down proteins or peptides, which are sequences of amino acids linked together in a chain.
In one such approach, through an in-licensing agreement with CytomX, scientists are leveraging the Probody™ technology in the development of therapeutic molecules with a protective peptide mask that keeps them from binding until they are inside the tumor environment, where specific activated proteases cut off the peptide to activate the drug.
“Once unmasked the antibody becomes active and binds to the intended target,” says Susan Morgan-Lappe, Ph.D., director of oncology discovery at AbbVie. “Utilizing this masking approach allows us to pursue targets that are not squeaky clean, or, put another way, because we are precisely directing these molecules to their targets, we are no longer limited to only considering targets that are mainly or exclusively expressed within diseased tissue sites.”
A Two-Stage Rocket
Another disease-targeting approach under preclinical investigation involves the use of conditional bispecific antibodies, antibodies that can bind to two different targets at different stages. Goodearl compares it to a two-stage rocket.
“These bispecific antibodies have two distinct domains,” Goodearl says. “One end of the molecule is the targeting antibody domain, the jet engine that lifts the rocket off of the planet and directs it to the right area; the other end is the activating domain, the protein piece that will go to work against the target,” Goodearl says.
Once the molecule arrives at the target, the linker connecting the two domains is cut by a protease and the jet engine targeting end of the molecule is jettisoned, leaving the activating piece to attack the tumor cells.
True Targeting Medicine
With research efforts in areas such as conditional activation rapidly advancing, Goodearl sees reasons to believe we are getting closer to more precisely targeted cancer medicines, as well as the potential to apply these approaches in diseases beyond cancer, including immune-mediated and neurological diseases.
“What we’re talking about here is targeted therapy in the truest sense of the word – to have medicines that go to work only where the diseased tissue is because we are properly directing the activation,” Goodearl says. “We are entering a stage that we hope will be transformative for patient treatment.”