5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.
Folate receptor-targeted PET radiotracers can potentially serve as versatile imaging agents for the diagnosis, staging, and prediction of response to therapy of patients with folate receptor (FR)-expressing cancers. Because current FR-targeted PET reagents can be compromised by complex labeling procedures, low specific activities, poor radiochemical yields or unwanted accumulation in FR negative tissues, we have undertaken to design an improved folate-PET agent that might be more amenable for clinical development. For this purpose, we have synthesized a folate-NOTAAl18F radiotracer and examined its properties both in vitro and in vivo. Methods Radiochemical synthesis of folate-NOTA-Al18F was achieved by incubating 18F− with AlCl3 for 2 min followed by heating in the presence of folate-NOTA for 15 min at 100 °C. Binding of folate-NOTA-Al18F to FR was quantitated in homogenates of KB and Cal51 tumor xenografts in the presence and absence of excess folic acid as a competitor. In vivo imaging was performed on nu/nu mice bearing either FR+ve (KB cell) or FR−ve (A549 cell) tumor xenografts, and specific accumulation of the radiotracer in tumor and other tissues was assessed by high-resolution micro-PET and ex vivo biodistribution in the presence and absence of excess folic acid. Image quality of folate-NOTA-Al18F was compared with that of 99mTc-EC20, a clinically established folate-targeted SPECT imaging agent. Results Total radiochemical synthesis and purification of folate-NOTA-Al18F was completed within 37 min, yielding a specific activity of 68.82±18.5 GBq/μmol, radiochemical yield of 18.6±4.5%, and radiochemical purity of 98.3±2.9%. Analysis of FR binding revealed a Kd of ~1.0 nM, and micro-PET imaging together with ex vivo biodistribution analyses demonstrated high FR-mediated uptake in an FR+ tumor and the kidneys. Conclusions Folate-NOTA-Al18F constitutes an easily prepared FR-targeted PET imaging agent with improved radiopharmaceutical properties and high specificity for folate receptor expressing tumors. Given its improved properties over 99mTc-EC20 (i.e. higher resolution, shorter image acquisition time, etc.), we conclude that folate-NOTA-Al18F constitutes a viable alternative to 99mTc-EC20 for use in identification, diagnosis, and staging of patients with FR-expressing cancers.
Activated macrophages play a significant role in initiation and progression of inflammatory diseases and may serve as the basis for the development of targeted diagnostic methods for imaging sites of inflammation. Folate receptor beta (FR-β) is differentially expressed on activated macrophages associated with inflammatory disease states yet is absent in either quiescent or resting macrophages. Because folate binds with high affinity to FR-β, development of folate directed imaging agents has proceeded rapidly in the past decade. However, reports of PET based imaging agents for use in inflammatory conditions remain limited. To investigate whether FR-β expressing macrophages could be exploited for PET based inflammatory imaging, two separate folate-targeted PET imaging agents were developed, 4-[(18)F]-fluorophenylfolate and [(68)Ga]-DOTA-folate, and their ability to target activated macrophages were examined in a rodent inflammatory paw model. We further compared inflamed tissue uptake with 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]-FDG). microPET analysis demonstrated that both folate-targeted PET tracers had higher uptake in the inflamed paw compared to the control paw. When these radiotracers were compared to [(18)F]-FDG, both folate PET tracers had a higher signal-to-noise ratio (SNR) than [(18)F]-FDG, suggesting that folate tracers may be superior to [(18)F]-FDG in detecting diseases with an inflammatory component. Moreover, both folate-PET imaging agents also bind to FR-α which is overexpressed on multiple human cancers. Therefore, these folate derived PET tracers may also find use for localizing and staging FR(+) cancers, monitoring response to therapy, and for selecting patients for tandem folate-targeted therapies.
Background: Fibrodysplasia ossificans progressiva (FOP), an ultra-rare disorder caused by mutations in the gene encoding activin A receptor type 1 (ACVR1), is characterized by painful flare-ups and cumulative heterotopic ossification (HO). Garetosmab, a fully-human monoclonal antibody blocking activin A, prevents HO in FOP mice. Methods: LUMINA-1 (NCT03188666) was a phase 2, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and effects on HO of intravenous (IV) garetosmab 10 mg/kg every 4 weeks (Q4W). Adult patients with FOP were randomized to garetosmab or placebo for 28 weeks (Period 1), followed by an open-label period (Period 2). After Period 2, patients were allowed to stay on garetosmab in an open-label extension. For Period 1, primary endpoints were HO total lesion activity (HO-TLA) by 18F-sodium fluoride positron emission tomography (18F-NaF PET) and HO total lesion volume by computed tomography (CT). The Period 2 primary endpoint compared the number of new lesions in Period 2 versus Period 1. The safety primary endpoint was incidence and severity of TEAEs through the end of the Period 1 at week 28. Findings: Patients (n=44) were randomized to garetosmab (n=20) or placebo (n=24). In Period_1, there was a trend for garetosmab to decrease HO-TLA versus placebo (24.6%; P=0.07), primarily driven by near complete prevention of new lesions (97% decrease by 18F-NaF PET, post-hoc P=0.009; 90% relative reduction by CT, post-hoc P=0.017); flare-ups were significantly reduced (P=0.0005). For placebo patients transitioning to garetosmab in Period 2, no patients developed new HO lesions (0% in Period 2 versus 40.9% in Period_1; P=0.0027) by CT. All 44 patients met primary safety endpoint of at least one TEAE during Period 1. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the AEs were predominantly mild in severity, with no effect on patients' ability to receive garetosmab. Five deaths (5/44; 11.4%) occurred either in Period 2 or the open-label extension. The deaths were associated with baseline disease severity in some, pre-existing comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods. Interpretation: Garetosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although side effects were mild to moderate, there were a relatively high number of deaths for a small study; the deaths were not related to epistaxis and considered unlikely to be related to garetosmab.
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