“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.”