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Highly sensitive PET imaging agents for quantitative tracking of gene and cell therapy
As gene/cell therapy becomes clinically routine, improved methods to image genetically engineered cells, including immunotherapy, are imperative. Clinicians are interested answering basic questions critical to determining response to cancer therapy such as: How many therapeutic cells are at the tumor? Is there off-target accumulation? Currently, there is no single agent that provides a facile tool for long-term cell tracking. Given the genetic manipulation inherent to gene therapy, a genetic imaging “handle” is a logical solution and positron emission tomography (PET) provides high sensitivity and spatial resolution. Standard radiotracer reporter proteins such as NIS and HSV1-tk and endogenous human receptor targets each have significant limitations.
Penn researchers have developed an alternative PET imaging strategy based on E. coli dihydrofolate reductase (Ec DHFR), and isotope modifications of its specific small molecule inhibitor, trimethoprim (TMP). The bacterial DHFR binding site is different than the human binding site, resulting in 3-orders of magnitude change in TMP affinity between the two proteins, suggesting a low background in unmodified human tissues and retention in Ec DHFR in engineered cells, ultimately providing high contrast imaging. [11C]TMP can be quickly translated into patients (same molecular structure as the antibiotic) and [18F]FPTMP has a 110 minute half-life, which allows better signal to noise (can be distributed to community hospitals by a regional radiopharmacy). Using small animal models of cell tracking, 11C and 18F TMP derivatives show robust signal to noise and great potential for improving gene/cell immunotherapy.
Stage of Development:
In vivo (mouse) data
Pending Provisional Application
Sellmyer et al. J Nucl Med, 2015
Docket # 15-7528