作者: Manwani, Deepa ; Sanchez-Olle, Gessami ; Kutlar, Abdullah ; Shah, Nirmish ; Liles, Darla ; Nair, Santosh M. ; Tanaka, Chiaki ; Brown, R. Clark ; Bodla, Shankaranand ; Kanter, Julie ; Albers, Urs ; Norris, Cynthia

Abstract:

Crizanlizumab is an anti–P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N = 45) and 7.5 mg/kg (N = 12) in patients with SCD with a history of VOCs. The median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion, and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only 1 event was deemed treatment-related (7.5 mg/kg group). No treatment-related serious AEs occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 “pain during infusion”), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug-related. No treatment-related bleeding events were reported. No patients developed immunogenicity. The median (range) absolute reduction from baseline in the annualized rate of VOCs leading to a health care visit was −0.88 (−14.7 to 13.3) and −0.93 (−2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in patients with SCD and the potential sustained efficacy and long-term safety of the drug after >12 months’ treatment. This trial was registered at www.clinicaltrials.gov as #NCT03264989.

2020-12-01·Journal of translational medicine2区 · 医学

P-selectin blockade ameliorates lupus nephritis in MRL/lpr mice through improving renal hypoxia and evaluation using BOLD-MRI

2区 · 医学

ArticleOA

作者: Zhang, Qianying ; Xu, Xueqin ; Chen, Sheng ; Shao, Shuxin ; Li, Xiao ; Wang, Weiming ; Zhang, Liwen ; Liu, Yan

Abstract:

Background:

Lupus nephritis is one of the most common and severe complications of systemic lupus erythematosus, of which poor prognosis is indicated by aggravated renal hypoxia and tubulointerstitial fibrosis. Cell adhesion molecules play a key role in the progression of lupus nephritis tubulointerstitial lesion, including P-selectin, which mediates the rolling of leukocytes and subsequent adhesion and infiltration and then initiates the inflammatory immune response and ischemia and hypoxia injury. However, the effects and mechanisms of P-selectin in lupus nephritis remain to be investigated, and a noninvasive measurement of lupus nephritis tubulointerstitial hypoxia and fibrosis remains to be explored.

Methods:

Thirty-four MRL/lpr mice were randomly divided into the following three groups: MRL/lpr, saline, and anti-P-selectin, which consisted of no treatment, treatment with normal saline, and treatment with anti-P-selectin monoclonal antibody (mAb) from 12 to 16 weeks of age, respectively. Ten male C57BL/6 mice of the same age served as normal controls. 24-h urinary protein, urinary albumin–creatinine ratio, and periodic acid–Schiff were used to assess kidney damage; Western blot or immunohistochemical staining of the hypoxia probe Hypoxyprobe™-1, hypoxia-inducible factor 1α (HIF-1α), and CD31 were used to evaluate hypoxia in renal tissue; and NADPH oxidase subunit gp91phox and p22phox were used to examine renal oxidative stress. The correlation between kidney injury and blood oxygen level–dependent magnetic resonance imaging (BOLD-MRI) was calculated to assess the clinical value of BOLD-MRI.

Results:

P-selectin is upregulated in lupus nephritis. Blocking P-selectin with mAb alleviated renal tubulointerstitial fibrosis, renal hypoxia, and peritubular capillary loss, without alteration of the levels of lupus activity indicators, anti-dsDNA antibody, or complement C3. BOLD-MRI showed that the reduced R2* values in the renal cortex and medulla of lupus mice were increased when treated with anti-P-selectin mAb as compared with those treated with normal saline, which were negatively correlated with Hypoxyprobe™-1 hypoxia probe and the expression of HIF-1α.

Conclusions:

Early intervention of lupus nephritis with anti-P-selectin mAb can significantly improve the hypoxic state of the kidney and reduce the severity of tubulointerstitial lesions. BOLD-MRI techniques are noninvasive and can dynamically evaluate the changes in renal lesions and intrarenal oxygenation levels before and after treatment in lupus nephritis.

2020-09-08·Blood advances2区 · 医学

Integrin VLA-4 as a PET imaging biomarker of hyper-adhesion in transgenic sickle mice

2区 · 医学

Article

作者: Little-Ihrig, Lynda ; Novelli, Enrico M ; Day, Kathryn E ; Tavakoli, Sina ; Anderson, Carolyn J ; Latoche, Joseph D ; Sundd, Prithu ; Zhu, Qin ; Perkins, Lydia A ; Nyiranshuti, Lea

Abstract:

In sickle cell disease (SCD), very late antigen-4 (VLA-4 or integrin α4β1) mediates the adhesion of reticulocytes to inflamed, proinflammatory endothelium, a key process in promoting vaso-occlusive episodes (VOEs). We hypothesized that a radionuclide tracer targeting VLA-4 could be harnessed as a positron emission tomography (PET) imaging biomarker of VOEs. We tested the VLA-4 peptidomimetic PET tracer 64Cu-CB-TE1A1P-PEG4-LLP2A (64Cu-LLP2A) for imaging hyper-adhesion–associated VOEs in the SCD Townes mouse model. With lipopolysaccharide (LPS)-induced VOEs, 64Cu-LLP2A uptake was increased in the bone marrow of the humeri and femurs, common sites of VOEs in SCD mice compared with non-SCD mice. Treatment with a proven inhibitor of VOEs (the anti-mouse anti-P-selectin monoclonal antibody [mAb] RB40.34) during LPS stimulation led to a reduction in the uptake of 64Cu-LLP2A in the humeri and femurs to baseline levels, implying blockade of VOE hyper-adhesion. Flow cytometry with Cy3-LLP2A demonstrated an increased percentage of VLA-4–positive reticulocytes in SCD vs non-SCD mice in the bone and peripheral blood after treatment with LPS, which was abrogated by anti-P-selectin mAb treatment. These data, for the first time, show in vivo imaging of VLA-4–mediated hyper-adhesion, primarily of SCD reticulocytes, during VOEs. PET imaging with 64Cu-LLP2A may serve as a valuable, noninvasive method for identifying sites of vaso-occlusion and may provide an objective biomarker of disease severity and anti-P-selectin treatment efficacy in patients with SCD.

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2023-02-06

·Pharmaceutical Technology

Feinstein Institutes researchers discover new protein for sepsis treatment

The new study was led by Feinstein Institutes researcher Haichao Wang. Credit: Northwell Health. Researchers at the Feinstein Institutes for Medical Research have discovered a new protein that can be a potential therapeutic target for lethal sepsis . Led by Feinstein Institutes researcher Haichao Wang, the new study focuses on detecting protein mediators that might contribute to uncontrolled immune responses to lethal infections. It explores the monoclonal antibody detection that may work against procathepsin-L (pCTS-L), a pro-inflammatory protein mediator, as the potential remedy. These anti-pCTS-L monoclonal antibodies may help in providing effective treatments for human sepsis as well as other infectious diseases, such as Covid-19. The researchers’ team created a pCTS-L-neutralising monoclonal antibodies panel, which effectively lowered the pCTS-L pro-inflammatory activities in human immune cell cultures and saved mice from lethal sepsis. Feinstein Institutes Institute of Molecular Medicine professor Dr Wang said: “Sepsis is a complex and fatal complication. Despite decades of research, there remains a lack of treatment. “The hope is that by identifying this new protein mediator to curb uncontrolled inflammation, new drugs may be developed to prevent unnecessary death in septic patients.” According to the Feinstein Institutes for Medical Research, sepsis affects approximately 50 million people globally and occurs when the immune system of the body triggers too much inflammation to help fight against infections. It noted that septic patients frequently show simultaneous pro and anti-inflammatory pathways occurrence, which may make them suffer from immunosuppression. The findings from the study have set a way for ‘translation’ clinical trials to test the new monoclonal antibody therapies that can be utilised for the treatment of septic patients. Feinstein Institutes president and CEO Kevin Tracey said: “The first step in drug discovery is identifying molecular targets. “Dr Wang’s research has done just that and opens new doors for exploring mechanisms to treat sepsis.”

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休克	临床2期	-	PDL BioPharma, Inc.	-
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再灌注损伤	临床前	美国	PDL BioPharma, Inc.	-
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