F8-IL10: A New Potential Antirheumatic Drug Evaluated by a PET-Guided Translational Approach | Zendy

Stefan Bruijnen | Zendy; Durga M. S. H. Chandrupatla | Zendy; Leonardo Giovani | Zendy; Dario Neri | Zendy; Daniëlle J. Vugts | Zendy; Marc C. Huisman | Zendy; Otto S. Hoekstra | Zendy; René J.P. Musters | Zendy; Adriaan A. Lammertsma | Zendy; Guus A.M.S. van Dongen | Zendy; Gerrit Jansen | Zendy; Carla F.M. Molthoff | Zendy; Conny J. van der Laken | Zendy

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F8-IL10: A New Potential Antirheumatic Drug Evaluated by a PET-Guided Translational Approach

Author(s) -

Stefan Bruijnen,

Durga M. S. H. Chandrupatla,

Leonardo Giovani,

Dario Neri,

Daniëlle J. Vugts,

Marc C. Huisman,

Otto S. Hoekstra,

René J.P. Musters,

Adriaan A. Lammertsma,

Guus A.M.S. van Dongen,

Gerrit Jansen,

Carla F.M. Molthoff,

Conny J. van der Laken

Publication year - 2018

Publication title -

molecular pharmaceutics

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.13

H-Index - 127

eISSN - 1543-8392

pISSN - 1543-8384

DOI - 10.1021/acs.molpharmaceut.8b00982

Subject(s) - biodistribution , medicine , spleen , interleukin 10 , rheumatoid arthritis , arthritis , interleukin 1 receptor antagonist , in vivo , pharmacokinetics , antibody , pharmacology , pathology , immunology , cytokine , receptor , antagonist , receptor antagonist , biology , microbiology and biotechnology

Antibody fragment F8-mediated interleukin 10 (IL10) delivery is a novel treatment for rheumatoid arthritis (RA). F8 binds to the extra-domain-A of fibronectin (ED-A). In this study, in vivo biodistribution and arthritis targeting of radiolabeled F8-IL10 were investigated in RA patients, followed by further animal studies. Therefore, three RA patients (DAS28 > 3.2) received 0.4 mg of 30-74 megabecquerel [ 124 I]I-F8-IL10 for PET-CT and blood sampling. In visually identified PET-positive joints, target-to-background was calculated. Healthy mice, rats, and arthritic rats were injected with iodinated F8-IL10 or KSF-IL10 control antibody. Various organs were excised, weighed, and counted for radioactivity. Tissue sections were stained for fibronectin ED-A. In RA patients, [ 124 I]I-F8-IL10 was cleared rapidly from the circulation with less than 1% present in blood after 5 min. PET-CT showed targeting in 38 joints (11-15 per patient) and high uptake in the liver and spleen. Mean target-to-background ratios of PET-positive joints were 2.5 ± 1.2, 1.5 times higher for clinically active than clinically silent joints. Biodistribution of radioiodinated F8-IL10 in healthy mice showed no effect of the radioiodination method. [ 124 I]I-F8-IL10 joint uptake was also demonstrated in arthritic rats, ∼14-fold higher than that of the control antibody [ 124 I]I-KSF-IL10 ( p < 0.001). Interestingly, liver and spleen uptake were twice as high in arthritic than in healthy rats and were related to increased (∼7×) fibronectin ED-A expression in these tissues. In conclusion, [ 124 I]I-F8-IL10 uptake was observed in arthritic joints in RA patients holding promise for visualization of inflamed joints by PET-CT imaging and therapeutic targeting. Patient observations and, subsequently, arthritic animal studies pointed to awareness of increased [ 124 I]I-F8-IL10 uptake in the liver and spleen associated with moderate systemic inflammation. This translational study demonstrated the value of in vivo biodistribution and PET-CT-guided imaging in development of new and potential antirheumatic drugs'.

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