Imaging the Alternatively Spliced D Domain of Tenascin C in a Preclinical Model of Inflammatory Bowel Disease

Zhang, Liang; Wang, Yuzhen; Homan, Kristoff T.; Gaudette, Stephanie M.; McCluskey, Andrew J.; Chan, Y.T.; Murphy, Joanne; Abdalla, Mary N.; Nelson, Christine M.; Sun, Victor; Erickson, Jon W.; Knight, Heather; Clabbers, Anca; Sterman, Annette J. Schwartz; Mitra, Soumya

doi:10.1007/s11307-022-01758-6

Cited by 3 publications

(1 citation statement)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although most immunocytokines aim to deliver a pro-inflammatory cytokine to the tumour, the platform's versatility can also direct anti-inflammatory cytokines to inflamed tissues. This is illustrated by the IL-22 immunocytokine (ABBV-022; out-licensed by Abbvie) which targets the gut mucosa for treatment of ulcerative colitis 120 .…”

Section: Routing Cytokines With Fusion Proteinsmentioning

confidence: 99%

Engineering cytokine therapeutics

Deckers¹,

Anbergen²,

Hokke

et al. 2023

Nat Rev Bioeng

View full text Add to dashboard Cite

Cytokines have pivotal roles in immunity, making them attractive as therapeutics for a variety of immune-related disorders. However, the widespread clinical use of cytokines has been limited by their short blood half-lives and severe side effects caused by low specificity and unfavourable biodistribution. Innovations in bioengineering have aided in advancing our knowledge of cytokine biology and yielded new technologies for cytokine engineering. In this Review, we discuss how the development of bioanalytical methods, such as sequencing and high-resolution imaging combined with genetic techniques, have facilitated a better understanding of cytokine biology. We then present an overview of therapeutics arising from cytokine re-engineering, targeting and delivery, mRNA therapeutics and cell therapy. We also highlight the application of these strategies to adjust the immunological imbalance in different immune-mediated disorders, including cancer, infection and autoimmune diseases. Finally, we look ahead to the hurdles that must be overcome before cytokine therapeutics can live up to their full potential.

show abstract

Section: Routing Cytokines With Fusion Proteinsmentioning

confidence: 99%

Engineering cytokine therapeutics

Deckers¹,

Anbergen²,

Hokke

et al. 2023

Nat Rev Bioeng

View full text Add to dashboard Cite

show abstract

Increased imaging ligand hydrophilicity and improved pharmacokinetic properties provides enhanced in vivo targeting of fibroblast activation protein

Narain,

Nessler,

Richardson

et al. 2024

npj Imaging

View full text Add to dashboard Cite

In this work, the impact of physicochemical modifications on pharmacokinetics and in vivo targeting of a small molecule fibroblast activation protein inhibitor (FAPI) imaging ligand in a murine model of rheumatoid arthritis was evaluated. While similar ligands have been well-reported in oncology for molecular imaging and radiotherapy, there are limited reports of FAPI derivatives in targeted applications in immunology. As inflammation may increase both specific and non-specific delivery of targeted agents in general, we sought to identify the optimal targeted molecular imaging probe characteristics for efficient cell surface engagement. A series of FAPI derivatives were synthesized and their physicochemical properties modified via conjugation of fluorescent dyes and/or an albumin-binding small molecule. The impact of these modifications on cell surface binding affinity was assessed using an overexpressing cell line. Additionally, a thorough mechanistic characterization of fibroblast activation protein (FAP) cell surface internalization was evaluated in both overexpressing and endogenously expressing cells. Lastly, the pharmacokinetics and in vivo uptake in inflamed arthritic paws were characterized via near-infrared (NIR) imaging. All targeted molecular imaging agents tested maintained strong nanomolar binding affinity to cell surface FAP independent of chemical modification. The murine fibroblast-like synoviocytes expressed lower absolute cell-surface FAP compared to a transfected line, and the net internalization half-life measured for the transfected cells via flow cytometry was 7.2 h. The unmodified FAPI ligand exhibited the poorest in vivo targeting, likely resulting from its large apparent volume of distribution (62.7 ml) and rapid systemic clearance (t1/2 = 0.5 h). Conjugation of a charged, hydrophilic AF647 fluorophore decreased systemic clearance (t1/2 = 2.1 h) and demonstrated a 2-fold improvement in blocking FAPI-800CW engagement of FAP in vivo when compared to blocking of FAPI-800CW with FAPI with up to 2.8-fold improvements noted for the equivalent albumin binding construct comparison.

show abstract

Increased Imaging Ligand Hydrophilicity and Improved Pharmacokinetic Properties Provides Enhanced In Vivo Targeting of Fibroblast Activation Protein

Narain,

Nessler,

Richardson

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

In this work, the impact of physicochemical modifications on pharmacokinetics and in vivo targeting of a small molecule fibroblast activation protein inhibitor (FAPI) imaging ligand in a murine model of rheumatoid arthritis was evaluated. While similar ligands have been well-reported in oncology for molecular imaging and radiotherapy, there are limited reports of FAPI derivatives in targeted applications in immunology. As inflammation may increase both specific and non-specific delivery of targeted agents in general, we sought to identify the optimal targeted molecular imaging probe characteristics for efficient cell surface engagement. A series of FAPI derivatives were synthesized and their physicochemical properties modified via conjugation of fluorescent dyes and/or an albumin-binding small molecule. The impact of these modifications on cell surface binding affinity was assessed using an overexpressing line. Additionally, a thorough mechanistic characterization of fibroblast activation protein (FAP) cell surface internalization was evaluated in both overexpressing and endogenously expressing cells. Lastly, the pharmacokinetics and in vivo uptake in inflamed arthritic paws were characterized via near-infrared (NIR) imaging. All targeted molecular imaging agents tested maintained strong nanomolar binding affinity to cell surface FAP independent of chemical modification. The murine fibroblast-like synoviocytes expressed lower absolute cell-surface FAP compared to a transfected line, and the net internalization half-life measured for the transfected cells via flow cytometry was 7.2 h. The unmodified FAPI ligand exhibited the poorest in vivo targeting, likely resulting from its large apparent volume of distribution (62.7 ml) and rapid systemic clearance (t1/2 = 0.5 h). Conjugation of a charged, hydrophilic AF647 fluorophore decreased systemic clearance (t1/2 = 2.1 h) and demonstrated a 2-fold improvement in blocking FAPI-800CW engagement of FAP in vivo when compared to blocking of FAPI-800CW with FAPI with up to 2.8-fold improvements noted for the equivalent albumin binding construct comparison.

show abstract

Imaging the Alternatively Spliced D Domain of Tenascin C in a Preclinical Model of Inflammatory Bowel Disease

Cited by 3 publications

References 54 publications

Engineering cytokine therapeutics

Engineering cytokine therapeutics

Increased imaging ligand hydrophilicity and improved pharmacokinetic properties provides enhanced in vivo targeting of fibroblast activation protein

Increased Imaging Ligand Hydrophilicity and Improved Pharmacokinetic Properties Provides Enhanced In Vivo Targeting of Fibroblast Activation Protein

Contact Info

Product

Resources

About