This proposal aims to develop an effective immunoPET agent for idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic lung disease with an average survival of only 2-3 years from the time of diagnosis. High resolution CT scanning can frequently diagnose IPF non-invasively with high specificity, but CT cannot accurately predict prognosis or responsiveness to therapeutic approaches currently under evaluation. IPF is a markedly heterogeneous disease both in disease progression and pathogenesis. Different pro-fibrotic pathways may be more or less activated in individual patients. This biological heterogeneity is the likely cause of failure of a large number of clinical trials aimed at pharmacological IPF therapy. Monoclonal antibodies (mAbs) are among the most promising candidates for IPF therapy with 5 mAbs currently in clinical development. One of these mAbs, STX-100, targets the ?v6 integrin and ?v6 inhibition has been demonstrated to prevent pulmonary fibrosis in animal models. Personalized medicine can greatly improve drug development for IPF and ultimately improve disease outcomes. Evaluation of target abundance, accessibility and drug uptake in individual patients by way of imaging provides an invaluable tool for the rapid and non-invasive identification of the potential response to therapy. ImmunoPET, where the antibody is labeled with a long-lived positron emitter such as the long-lived PET isotope Zr-89 (t1/2 = 78 h), represents a clinically translatable approach to better characterizing disease and treatment response. In this project we will develop new bifunctional chelators for radiolabeling and immunoconjugation with Zr-89 and compare this new technology with the state of the art. We will apply the best chelators identified to the development of an immunoPET probe targeting the ?v6 integrin. The ?v6-targeted immunoPET probe will be used to address 4 key questions regarding mAb-based therapy for IPF and pulmonary pathobiology: 1) Can ?v6-targeted immunoPET be used to noninvasively detect pulmonary fibrosis and does probe uptake correlate with disease progression? 2) Can immunoPET be used to monitor treatment response in an IPF mouse model, and are the changes detected by PET observed prior to changes in fibrotic burden? 3) In a heterogeneous disease like IPF, can the intravenous mAb therapy reach all of its biological target? 4) Does ?v6 expression vary among different models of pulmonary fibrosis when the underlying nidus is different? The output of this work will be development of an ?v6-targeted immunoPET probe that can be translated to clinical trials, as well as optimized Zr-89 labeling technology for general immunoPET applications.
Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic, fatal lung disease with an average survival of only 2-3 years from the time of diagnosis. This proposal aims to develop a positron emission tomography probe to noninvasively diagnose IPF, stage disease, monitor therapy response, and potentially select patients that would benefit from new treatments for IPF currently in clinical trials.
| Boros, Eszter; Srinivas, Raja; Kim, Hee-Kyung et al. (2017) Intramolecular Hydrogen Bonding Restricts Gd-Aqua-Ligand Dynamics. Angew Chem Int Ed Engl 56:5603-5606 |
