Preclinical Development of SHR-1819, a Potent Humanized IL-4Rα Antibody for Treating Type 2 Inflammatory Diseases.

Background: Interleukin (IL)-4 and IL-13 are critical pathogenic factors for type 2 inflammation-related allergic diseases, sharing the mutual receptor subunit IL-4Rα. However, it was ineffective for certain type 2 inflammation diseases by targeting IL-4, IL-13 ligand alone or both in clinical studies. The work presented herein aimed to evaluate the preclinical efficacy and pharmacokinetics profile of a novel monoclonal antibody against IL-4Rα, SHR-1819, as a promising therapy for type 2 inflammation diseases. Methods: SHR-1819 was generated through immunization by C57BL/6 mice with recombinant hIL-4Rα protein, followed by humanization and affinity maturation. Then, its binding properties with IL-4Rα were determined using surface plasmon resonance (SPR) and ELISA. In vitro inhibitory effects of SHR-1819 were assessed on hIL-4-/hIL-13-induced cell proliferation and signal transducer and activator of transcription 6 (STAT6) signaling activation. In vivo efficacy of SHR-1819 was evaluated in several type 2 inflammatory diseases models, including asthma, atopic dermatitis (AD), and allergic rhinitis (AR) by using hIL-4/hIL-4Rα transgenic mice. Furthermore, the pharmacokinetic (PK) profiles of SHR-1819 were characterized. Results: SHR-1819 showed high binding affinity to human IL-4Rα and effectively blocked IL-4Rα at sub-nanomolar concentration. In vitro assays indicated that SHR-1819 significantly inhibited TF-1 cell proliferation and STAT6 activation induced by hIL-4/hIL-13. In the asthma model, SHR-1819 could reduce airway hyperresponsiveness, decrease serum IgE levels, and alleviated inflammatory lung cell infiltration. In the AD model, SHR-1819 could significantly alleviate inflammatory and skin symptoms. In the AR model, it could remarkably decrease the frequencies of nasal rubbing and sneezing, and inflammatory cell infiltration in nasal tissues. These in vivo efficacy studies demonstrated the therapeutic potential of SHR-1819 in preclinical disease models. Moreover, subcutaneous administration of SHR-1819 exhibited favorable bioavailability in mice. Conclusion: The results supported SHR-1819 as a promising preclinical candidate for the treatment of type 2 inflammatory diseases, including asthma, AD and AR.

Enhanced Biphasic Reactions in Amphiphilic Silica Mesopores.

In this study, we investigated the effect of the pore volume and mesopore size of surface-active catalytic organosilicas on the genesis of particle-stabilized (Pickering) emulsions for the dodecanal/ethylene glycol system and their reactivity for the acid-catalyzed biphasic acetalization reaction. To this aim, we functionalized a series of fumed silica superparticles (size 100-300 nm) displaying an average mesopore size in the range of 11-14 nm and variable mesopore volume, with a similar surface density of octyl and propylsulfonic acid groups. The modified silica superparticles were characterized in detail using different techniques, including acid-base titration, thermogravimetric analysis, TEM, and dynamic light scattering. The pore volume of the particles impacts their self-assembly and coverage at the dodecanal/ethylene glycol (DA/EG) interface. This affects the stability and the average droplet size of emulsions and conditions of the available interfacial surface area for reaction. The maximum DA-EG productivity is observed for A200 super-SiNPs with a pore volume of 0.39 cm3·g-1 with an interfacial coverage by particles lower than 1 (i.e., submonolayer). Using dissipative particle dynamics and all-atom grand canonical Monte Carlo simulations, we unveil a stabilizing role of the pore volume of porous silica superparticles for generating emulsions and local micromixing of immiscible dodecanal and ethylene glycol, allowing fast and efficient solvent-free acetalization in the presence of Pickering emulsions. The micromixing level is interrelated to the adsorption energy of self-assembled particles at the DA/EG interface.

Assessment of Visual Function with Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa in the Randomized XIRIUS Phase 2/3 Study.

PURPOSE: Cotoretigene toliparvovec (BIIB112/AAV8-RPGR) is an investigational vector-based gene therapy designed to provide a full-length, codon-optimized retinitis pigmentosa GTPase regulator (RPGR) protein to individuals with RPGR-associated X-linked retinitis pigmentosa (XLRP). We assessed efficacy and tolerability of cotoretigene toliparvovec subretinal gene therapy. DESIGN: Part 2 of the XIRIUS trial (ClinicalTrials.gov identifier, NCT03116113) was a phase 2/3, 12-month, randomized (1:1:1) dose-expansion study. PARTICIPANTS: Male patients ≥10 years of age with RPGR-associated XLRP were included. METHODS: Participants were randomized 1:1:1 to receive low-dose subretinal cotoretigene toliparvovec (5 × 1010 vector genomes/eye), high-dose cotoretigene toliparvovec (2.5 × 1011 vector genomes/eye) or to be an untreated control participant. MAIN OUTCOME MEASURES: The primary end point was the percentage of participants meeting microperimetry responder criteria (≥ 7-dB improvement at ≥ 5 of 16 central loci). Secondary end points included change from baseline in retinal sensitivity at the central 16 loci and the entire 68 loci at 12 months and change from baseline in low-luminance visual acuity (LLVA) at 12 months, as well as the proportion of eyes with a ≥ 15-Early Treatment Diabetic Retinopathy Study ETDRS letter LLVA and ≥ 10-ETDRS letter LLVA change from baseline at month 12. RESULTS: Because of the impact of the COVID-19 pandemic, enrollment ended before reaching the initial target, leaving the trial underpowered. Twenty-nine participants were included (low-dose group, n = 10; high-dose group, n = 10; control group, n = 9). At month 12, the percentage of participants meeting microperimetry responder criteria was not significantly different between either cotoretigene toliparvovec group (low dose, 37.5% [P = 0.3181]; high dose, 25.0% [P = 0.5177]) and the control group (22.2%). However, the mean change from baseline in microperimetry sensitivity improved significantly with the low-dose group versus the control group at month 12 (P = 0.0350). Significant improvement in LLVA occurred in the low-dose group versus the control group at month 12 (33.3% difference [80% confidence interval, 14.7%-55.2%]; P = 0.0498). Three ocular-related serious adverse events (SAEs) occurred in the low-dose group versus 7 SAEs in the high-dose group. CONCLUSIONS: The primary microperimetry end point was not met. Significant improvements in LLVA and mean microperimetry were observed compared with controls and fewer SAEs occured with low-dose compared with high dose cotoretigene toliparvovec. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Three-dimensional modelling and hemodynamic simulation of the closure of multiple entry tears in type B aortic dissection.

BACKGROUND: Stanford type B aortic dissection (TB-AD) is a life-threatening vascular condition with high rates of morbidity and mortality. Currently, thoracic endovascular aortic repair (TEVAR) is widely performed to treat TB-AD, and some studies have analyzed the influence of stents on hemodynamics using computational fluid dynamics (CFD) models. However, the accuracy of TB-AD simulation models are not satisfactory, they are often constructed as a regular ideal model. Furthermore, it is unclear which tear should be closed for the best treatment when there are multi entry tears. PURPOSE: The aims of this paper were to provide an assessment method for the selection of the surgical closure location for type B aortic dissection. Five 3D models of multiple entry tears in type B aortic dissection were produced using real patient computed tomography (CT) images to perform hemodynamic analyses of flow velocity streamlines, wall pressure, and wall shear stress. METHODS: A Boolean operation was adopted to establish 3D models with multiple entry tears in type B aortic dissection based on patient-specific CT images. The Mimics and Ansys plug-in The Integrated Computer Engineering and Manufacturing code for Computational Fluid Dynamics (ICEM CFD) software were applied to mesh the 3D models. The flow velocity streamlines, wall pressures, and wall shear stresses were then analyzed in the finite element analysis software Fluent. Five 3D models were produced to compare the hemodynamic characteristics of different entry tear numbers, as well as the changes of different closure positions before and after closure. RESULTS: The false lumen of the model with two entry tears had a higher wall pressure than that of model with multiple entry tears, which may tend to squeeze the true lumen and expand the false lumen. The load distribution of the vessel in the model with multiple entry tears had a more balanced flow velocity, and its wall pressure and shear stress were lower than that of model with two entry tears. For aortic dissection with two entry tears, the closure of the proximal entry tear was recommended, which helped to isolate and thrombose the false lumen, thereby improving the blood supply function of the true lumen. Because the postoperative vascular flow velocity and mechanical load performance of the vascular wall were still higher than those of normal blood vessels, the postoperative blood vessels remained pathological, and TEVAR did not restore the blood vessels to their original healthy state. CONCLUSIONS: Type B aortic dissection with two entry tears tend to squeeze the true lumen and expand the false lumen, resulting in a new entry tear and deterioration into multiple entry type B aortic dissection. The model of the vessel with multiple entry tears had a more balanced distribution in flow velocity and a smaller wall pressure and shear stress than that of the vessel with two entry tears. The closure of the proximal entry tear was considered an ideal solution for type B aortic dissection with two entry tears.

Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial.

Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41 .

Inhalable siRNA Nanoparticles for Enhanced Tumor-Targeting Treatment of KRAS-Mutant Non-Small-Cell Lung Cancer.

Kirsten rat sarcoma (KRAS) is the most commonly mutated oncogene in lung cancers. Gene therapy is emerging as a promising cancer treatment modality; however, the systemic administration of gene therapy has been limited by inefficient delivery to the lungs and systemic toxicity. Herein, we report a noninvasive aerosol inhalation nanoparticle (NP) system, termed "siKRAS@GCLPP NPs," to treat KRAS-mutant non-small-cell lung cancer (NSCLC). The self-assembled siKRAS@GCLPP NPs are capable of maintaining structural integrity during nebulization, with preferential distribution within the tumor-bearing lung. Inhalable siKRAS@GCLPP NPs show not only significant tumor-targeting capability but also enhanced antitumor activity in an orthotopic mouse model of human KRAS-mutant NSCLC. The nebulized delivery of siKRAS@GCLPP NPs demonstrates potent knockdown of mutated KRAS in tumor-bearing lungs without causing any observable adverse effects, exhibiting a better biosafety profile than the systemic delivery approach. The results present a promising inhaled gene therapy approach for the treatment of KRAS-mutant NSCLC and other respiratory diseases.

Controllable EIT-like mode splitting in a chiral microcavity.

Two coupled resonance modes can lead to exotic transmission spectra due to internal interference processes. Examples include electromagnetically induced transparency (EIT) in atoms and mode splitting in optics. The ability to control individual modes plays a crucial role in controlling such transmission spectra for practical applications. Here we experimentally demonstrate a controllable EIT-like mode splitting in a single microcavity using a double-port excitation. The mode splitting caused by internal coupling between two counter-propagating resonances can be effectively controlled by varying the power of the two inputs, as well as their relative phase. Moreover, the presence of asymmetric scattering in the microcavity leads to chiral behaviors in the mode splitting in the two propagating directions, manifesting itself in terms of a Fano-like resonance mode. These results may offer a compact platform for a tunable device in all-optical information processing.

A Phase IIb Randomized Clinical Study of an Anti-αvß6 Monoclonal Antibody in Idiopathic Pulmonary Fibrosis.

Rationale: Treatment options for idiopathic pulmonary fibrosis (IPF) are limited. Objectives: To evaluate the efficacy and safety of BG00011, an anti-αvß6 IgG1 monoclonal antibody, in the treatment of patients with IPF. Methods: In a phase IIb randomized, double-blind, placebo-controlled trial, patients with IPF (FVC ⩾50% predicted, on or off background therapy) were randomized 1:1 to once-weekly subcutaneous BG00011 56 mg or placebo. The primary endpoint was FVC change from baseline at Week 52. Because of early trial termination (imbalance in adverse events and lack of clinical benefit), endpoints were evaluated at Week 26 as an exploratory analysis. Measurements and Main Results: One hundred six patients were randomized and received at least one dose of BG00011 (n = 54) or placebo (n = 52). At Week 26, there was no significant difference in FVC change from baseline between patients who received BG00011 (n = 20) or placebo (n = 23), least squares mean (SE) -0.097 L (0.0600) versus -0.056 L (0.0593), respectively (P = 0.268). However, after Week 26, patients in the BG00011 group showed a worsening trend. Eight (44.4%) of 18 who received BG00011 and 4 (18.2%) of 22 who received placebo showed worsening of fibrosis on high-resolution computed tomography at the end of treatment. IPF exacerbation/or progression was reported in 13 patients (all in the BG00011 group). Serious adverse events occurred more frequently in BG00011 patients, including four deaths. Conclusions: The results do not support the continued clinical development of BG00011. Further research is warranted to identify new treatment strategies that modify inflammatory and fibrotic pathways in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT03573505).

Inhaled siRNA nanoparticles targeting IL11 inhibit lung fibrosis and improve pulmonary function post-bleomycin challenge.

Interleukin-11 (IL-11) is a profibrotic cytokine essential for the differentiation of fibroblasts into collagen-secreting, actin alpha 2, smooth muscle-positive (ACTA2+) myofibroblasts, driving processes underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we developed an inhalable and mucus-penetrative nanoparticle (NP) system incorporating siRNA against IL11 (siIL11@PPGC NPs) and investigated therapeutic potential for the treatment of IPF. NPs are formulated through self-assembly of a biodegradable PLGA-PEG diblock copolymer and a self-created cationic lipid-like molecule G0-C14 to enable efficient transmucosal delivery of siIL11. Noninvasive aerosol inhalation hindered fibroblast differentiation and reduced ECM deposition via inhibition of ERK and SMAD2. Furthermore, siIL11@PPGC NPs significantly diminished fibrosis development and improved pulmonary function in a mouse model of bleomycin-induced pulmonary fibrosis without inducing systemic toxicity. This work presents a versatile NP platform for the locally inhaled delivery of siRNA therapeutics and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including IPF.