Putting the Pieces Together
But an idea for a powerful application wasn't too far behind.
To illustrate the reactive immunization work during presentations to students and colleagues, Barbas created a simple slide. The image showed the mechanism of the catalytic activity. In chemical terms, it showed an R group attached to a diketone. The diketone, Barbas would note in his talks, leads to self-assembly of the substrate and antibody to form a complex.
In another project in the Barbas laboratory, the scientists happened to be exploring the potential of antibodies in cancer therapy. Because of this work, Barbas was aware that many pharmaceutical companies had tried to develop compounds against integrin molecules (a large and important family of adhesion molecules that promote stable interactions between cells and their environment), but that these projects had all run up against the same roadblock.
While potential therapeutics bound to the cancer integrin molecules with high affinity and specificity, the compounds were quickly cleared from the bodyXin some cases, in as short a period as 15 minutes. Especially for a chronic indication such as cancer, this rendered the compounds impractical for use as drugs, because they were difficult to administer often enough or in large enough quantities to produce a therapeutic effect.
Then one day, looking at the slide he had used for years in describing reactive immunization, Barbas suddenly got an idea. He saw a way to put together one of these integrin-targeting drugs with a catalytic antibody.
"Looking back at the slide, I thought, 'What if I just took that small molecule from the literature that binds these integrins, and put a diketone on it. If it attaches itself to the antibody, it would circulate for a long time."
1,000-Fold Increase in Therapeutic Effect
In the lab, Barbas, Lerner,
|Contact: Keith McKeown|
Scripps Research Institute