99mTc-NTP 15-5 is a companion radiotracer for assessing joint functional response to sprifermin (rhFGF-18) in a murine osteoarthritis model

Abstract

With the emergence of disease modifying osteoarthritis drugs (DMOAD), imaging methods to quantitatively demonstrate their efficacy and to monitor osteoarthritis progression at the functional level are urgently needed. Our group showed that articular cartilage can be quantitatively assessed in nuclear medicine imaging by our radiotracer 99mTc-NTP 15-5 targeting cartilage proteoglycans. In this work, surgically induced DMM mice were treated with sprifermin or saline. We investigated cartilage remodelling in the mice knees by 99mTc-NTP 15-5 SPECT-CT imaging over 24 weeks after surgery, as wells as proteoglycan biochemical assays. OA alterations were scored by histology according to OARSI guidelines. A specific accumulation of 99mTc-NTP 15-5 in cartilage joints was evidenced in vivo by SPECT-CT imaging as early as 30 min post-iv injection. In DMM, 99mTc-NTP 15-5 accumulation in cartilage within the operated joints, relative to contralateral ones, was observed to initially increase then decrease as pathology progressed. Under sprifermin, 99mTc-NTP 15-5 uptake in pathological knees was significantly increased compared to controls, at 7-, 12- and 24-weeks, and consistent with proteoglycan increase measured 5 weeks post-surgery, as a sign of cartilage matrix remodelling. Our work highlights the potential of 99mTc-NTP 15-5 as an imaging-based companion to monitor cartilage remodelling in OA and DMOAD response.

Assessment of 99mTc-NTP 15-5 uptake on cartilage, a new proteoglycan tracer: Study protocol for a phase I trial (CARSPECT)

“…Functional imaging such as proteoglycan tracer scintigraphy could be used to identify patient subgroups with PG altered cartilage, for which joint prosthesis is expected to really improve articular function and mobility. A recent preclinical study in a murine destabilization of medial meniscus model, highlights the potential of 99m Tc-NTP 15-5 as an imaging-based companion to monitor cartilage remodeling in osteoarthritis and response to the disease-modifying osteoarthritis drug, sprifermin (rhFGF-18), one of the most promising anabolic agents that have demonstrated cartilage repair properties in patients ( 8 ).…”

“…Numerous preclinical studies have shown its relevance in molecular imaging of cartilaginous pathologies such as osteoarthritis ( 2 , 4 ), inflammatory disease ( 6 ), and chondrosarcoma ( 7 ). 99m Tc-NTP 15-5 nuclear imaging was recently used in the murine destabilization of medial meniscus models, to monitor in vivo cartilage remodeling in response to disease-modifying osteoarthritis drugs (DMOAD) ( 8 ). Diagnosis of cartilaginous biochemical alterations could enable in vivo studies of joint functionality ( 9 ), which cannot be evaluated by conventional imaging techniques such as CT and MRI ( 10 , 11 ).…”

Sprifermin for Treatment of Osteoarthritis: Recombinant Fibroblast Growth Factor 18 as a Possible Disease-Modifying Knee Osteoarthritis Drug

“…injection and was still detectable up to 28 days post-injection, while its levels in other organs and tissues were low and no intact, undegraded sprifermin could be detected in the systemic blood [80]. Recently it was shown in a surgical mouse OA model by 99mTc-NTP 15-5 SPECT-CT imaging, which allows for monitoring of proteoglycan remodeling, that under sprifermin 99mTc-NTP 15-5 uptake in OA knees was significantly increased compared to controls in parallel with proteoglycan [81]. In fetlock joints of horses, in which a cartilage defect was induced, and which were thereafter subjected to microfracture treatment (a common surgical technique to enhance cartilage healing at the site of injury), i.a.…”

Osteoarthritis: Insights into Diagnosis, Pathophysiology, Therapeutic Avenues, and the Potential of Natural Extracts

“…Diseasemodifying OA drugs (DMOADs) are a group of molecules capable of intervening in specific molecular mediators of these processes. Among the most promising targets are matrix metalloproteinases such as MMP-13 protease or ADAMTS-4 and -5 peptidase, growth factors like fibroblast growth factor-18 (FGF-18), bone morphogenetic protein (BMP-7), or TGF-β, cytokines, and small molecule like TNF-α or IL-1β [183][184][185][186][187][188][189][190][191][192].…”