In this fast-track re-submission for re-classification (due to investigator move from academia to industry) of a multi-center, multi-disciplinary project, we will develop a targeted optical contrast agent and improved roomlight imaging system which allow for real-time imaging of surface tumors as small as 0.1 mm (and subsurface tumors as small as 1 mm to a depth of 5 mm) exposed at the excisional margin during radical prostatectomy surgery. Such tumors are now undetectable in real time. Residual tumor at the surgical margin occurs in 30% of all prostatectomies; such patients have a significantly higher risk of local recurrence, metastasis, and death, and require additional radiation therapy. The contrast agent is based on a conjugation of a Cy 7, a fluorescent dye, and huJ-591, a humanized antibody from Millennium Pharmaceuticals targeted to all cells of luminal prostate origin. We will synthesize this agent, test in tissue culture and xenograft mouse, GMP manufacture, and perform pre-clinical safety studies. This project divides into feasibility (R43) and development (R44) phases, in response to NCI/BIP PAR-03-125.
Specific aims of the 1 yr. R43 feasibility component are: a) to produce a targeted optical contrast agent specific for human prostate cells of luminal origin by conjugating Cy 7 to huJ591, b) to test a room-light clinical imaging system that detects a fluorescent signal in operating room ambient light from at a dye concentration expected to be found in tumors in vivo, with quantitative, milestone-based performance characteristics selected so as to make success in vivo likely, and c) to demonstrate that this agent can be detected with a signal to noise of at least 2:1 in 10 seconds or less, and imaged at nM levels in tissue models, while retaining 20% huJ591 binding activity.
This specific aims by which we will measure the success of the 3 year R44 development component are: a) to optimize dye kinetics, b) to deploy an OR-ready real-time imaging system, c) to produce a GMP pharmaceutical grade conjugated antibody-dye, and to perform pre-clinical safety testing in culture and in animals, and d) to evaluate performance in OR conditions, and e) quantitate the ability to surgically obtain negative margins in animal studies. If successful, this approach may lead to fewer positive margins during surgical prostatectomy and, in the long term, allow for more effective treatment, with ultimate extension to breast cancer and melanoma as well.
