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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
5K99HL125728-02
Application #
9146368
Study Section
Special Emphasis Panel (ZHL1-CSR-P (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2015-09-18
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2016
Total Cost
$173,800
Indirect Cost
$12,800
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Boros, Eszter; Holland, Jason P (2018) Chemical aspects of metal ion chelation in the synthesis and application antibody-based radiotracers. J Labelled Comp Radiopharm 61:652-671
Adams, Casey J; Wilson, Justin J; Boros, Eszter (2017) Multifunctional Desferrichrome Analogues as Versatile 89Zr(IV) Chelators for ImmunoPET Probe Development. Mol Pharm 14:2831-2842
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
Knopf, Kevin M; Murphy, Brendan L; MacMillan, Samantha N et al. (2017) In Vitro Anticancer Activity and in Vivo Biodistribution of Rhenium(I) Tricarbonyl Aqua Complexes. J Am Chem Soc 139:14302-14314
Boros, Eszter; Holland, Jason P; Kenton, Nathaniel et al. (2016) Macrocycle-Based Hydroxamate Ligands for Complexation and Immunoconjugation of (89)Zirconium for Positron Emission Tomography (PET) Imaging. Chempluschem 81:274-281
Iki, Nobuhiko; Boros, Eszter; Nakamura, Mami et al. (2016) Gd3TCAS2: An Aquated Gd(3+)-Thiacalix[4]arene Sandwich Cluster with Extremely Slow Ligand Substitution Kinetics. Inorg Chem 55:4000-5
Meimetis, Labros G; Boros, Eszter; Carlson, Jonathan C et al. (2016) Bioorthogonal Fluorophore Linked DFO-Technology Enabling Facile Chelator Quantification and Multimodal Imaging of Antibodies. Bioconjug Chem 27:257-63