In vivo imaging is rapidly gaining popularity as a faster and less expensive method for enhancing drug discovery and development. Its keen ability to noninvasively gauge drug efficacy and trail compounds inside living organisms places it at the forefront of new technologies. It could eventually replace traditional survival-based endpoints, especially since the FDA now accepts surrogate endpoints to prove drug efficacy.
Scientists at Cambridge Healthtech’s “In Vivo Molecular Imaging” meeting held late last year highlighted new research and insights into this burgeoning field. These include development of novel targeted tracers, new methods for cost-effective optical imaging, and functional imaging driven by positron emission tomography (PET) and its close cousin SPECT (single photon emission computed tomography).
Angiogenesis takes place in many pathological processes that range from cancer to myocardial infarctions. Vascular endothelial growth factor (VEGF) and its receptors play a critical role in angiogenesis. Consequently, this signaling pathway is the therapeutic target for several approved and a multitude of experimental antiangiogenic drugs.
Joseph Backer, Ph.D., CEO at SibTech (www.sibtech.com), is pursuing molecular imaging of VEGF receptors with targeted tracers. “VEGF receptors are major drug targets, so clinical imaging of these receptors will be valuable for diagnostics, patient segmentation, monitoring treatments, and developing drug regimens.”
Dr. Backer said that SibTech is converting growth factors such as VEGF into targeting vectors for contrast agent delivery. “The use of tracers based on growth factors is important because they can be delivered into targeted cells only by active receptors. Therefore, imaging with such tracers would provide information regarding receptor functionality.”
One challenge to this strategy has been the small size of growth factors. “With something that small, where evolution stringently selected each amino acid, it is a problem to find safe sites for attaching contrast agents. To solve this problem, we have developed a short fusion tag containing cysteine (Cys-tag) for site-specific derivatization.”
As it turns out, different proteins can be expressed with this tag and then safely and site specifically derivatized with a variety of imaging and therapeutic payloads. “In collaboration with Stanford University, and with support from NIH/NCI SBIR grants, we use Cys-tagged single-chain VEGF as a standardized platform for developing tracers for PET, SPECT, and near-infrared fluorescent imaging modalities,” noted Dr. Backer.
Currently, there are no contrast agents for imaging VEGF receptors. “We expect molecular imaging of VEGF receptors with our scVEGF-based strategies will greatly facilitate progress in development of anti-angiogenic therapies. We plan to take our lead SPECT tracer, scVEGF/99mTc, into clinical trials soon.”