Principles of the therapeutic use of monoclonal antibodies in oncology

Monoclonal antibodies have reached the stage of therapeutic agents, mostly in oncology, as illustrated by their wide use in lymphoma, breast cancer or colorectal cancer. The unravelling of their mechanisms of action and their interactions with their cellular receptors allows us to engineer new classes of therapeutic antibodies with increased efficacy. The identification of some of the tumour escape mechanisms may also help to define new approaches for patient selection and immunomonitoring. The present review addresses these various aspects.     

Effect of anti-TNFalpha treatment on circulating endothelial progenitor cells (EPCs) in rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, which may be attenuated by anti-inflammatory treatment. Endothelial progenitor cells (EPCs) have the ability to differentiate into mature endothelium and have a potentially reparative role protecting against ischemia and atherosclerosis. OBJECTIVE: To investigate the effect of treatment with infliximab on the number and functional capacity of endothelial progenitor cells (EPCs) in patients with RA, as a possible mechanism for reducing cardiovascular morbidity in this disorder. METHODS: Patients: Active seropositive RA patients (N = 14) considered candidates for starting infliximab treatment, were recruited. Assessment, based on DAS-28, was performed before treatment and 14 days later. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by the colony-forming unit (CFU) method. Endothelial phenotyping of CFU was performed by immunofluorescence employing antibodies to Tie-2 VEGF-receptor 2, and CD31. EPC Functional properties were evaluated by fibronectin adherance. RESULTS: A significant 33.4% increase (p < 0.001) in EPC levels was observed after infliximab. A 60% increase was noted in the EPC differentiation scale, (p < 0.002) while a 37.6% increase was observed in mean EPC adhesion (p < 0.001). These changes were associated with a 17.5% decrease in the DAS-28 (p < 0.0001). A significant correlation was observed between the clinical response, reflected by changes in DAS-28 and the degree of increase in EPC CFUs. CONCLUSION: A single dose of infliximab improved the number and functional properties of EPCs, in parallel with an early clinical effect, suggesting a possible mechanism by which anti-inflammatory treatment may reduce cardiovascular risk in RA patients.     

Monoclonal antibodies: technology around the clock for new therapeutic hopes

Engineering monoclonal antibodies, now widely used in the clinic, has made it possible to develop a new generation of antibodies with optimized functional properties. These antibodies should allow a significant improvement of the treatment of diseases where only few drugs are available, if any. However, the cost of treatments with monoclonal antibodies requires further improvements in production and purification technologies, and raises the question of generic antibodies. The present review summarizes some of the technological past and present challenges in the field.     

益生菌治疗类风湿关节炎的meta分析和试验序贯分析

系统评价益生菌治疗类风湿关节炎的临床疗效。

检索中国生物医学数据库、中国知网、万方、维普、Embase、PubMed、the Cochrane Library、Web of Science数据库,时间均从建库至2021年7月,对公开发表的益生菌治疗类风湿关节炎的随机对照试验进行meta分析和试验序贯分析。

共纳入6项研究,总样本量242例。Meta分析显示,益生菌治疗类风湿关节炎能显著降低CRP[MD = ‒2.26,95% CI = （‒4.30,‒0.23）,P = 0.03]和TNF-α[MD = ‒1.78,95% CI = （‒2.73,0.83）,P＜0.01]水平,提高IL-10[MD = 3.80,95% CI = （0.40,7.19）,P = 0.03]水平,而ESR、IL-1β、IL-6、MDA、TAC、DAS28、TJC、SJC、HAQ和ACR20等水平均与安慰剂相当。敏感性分析显示结果较为稳健,试验序贯分析显示CRP的获益具有结论性,Egger检验显示不存在发表偏倚（P = 0.17）。

益生菌能够有效降低CRP和TNF-α水平,提高IL-10水平,具有治疗类风湿关节炎的潜力。

     

Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial

BackgroundSarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex. In the MOBILITY phase III randomized controlled trial (RCT), sarilumab + methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR). These analyses indicate the effects of sarilumab + MTX versus placebo on patient-reported outcomes (PROs) in this RCT.MethodsPatients (n = 1197) were randomized to receive placebo, sarilumab 150 or 200 mg subcutaneously + MTX every 2 weeks for 52 weeks; after 16 weeks, patients without ≥20 % improvement from baseline in swollen or tender joint counts on two consecutive assessments were offered open-label treatment. PROs included patient global assessment of disease activity (PtGA), pain, health assessment questionnaire disability index (HAQ-DI), Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F). Changes from baseline at weeks 24 and 52 were analyzed using a mixed model for repeated measures. Post hoc analyses included percentages of patients reporting improvements equal to or greater than minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36. Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24.ResultsBoth doses of sarilumab + MTX vs placebo + MTX resulted in improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p < 0.0001) that was clinically meaningful, and persisted until week 52. In post hoc analyses, the percentages of patients with improvement equal to or greater than the MCID across all PROs were greater with sarilumab than placebo (p < 0.05), with differences ranging from 11.6 to 26.2 %, as were those reporting equal to or greater than normative scores.ConclusionsIn this RCT in patients with MTX-IR RA, sarilumab + MTX resulted in sustained improvement in PROs that were clinically meaningful, greater than placebo + MTX, and complement the previously reported clinical efficacy and safety of sarilumab.

Trial registration

ClinicalTrials.gov. NCT01061736. February 2, 2010     

Astrocyte elevated gene-1 promotes inflammation and invasion of fibroblast-like synoviocytes in rheumatoid arthritis

Astrocyte elevated gene-1 (AEG-1) was initially induced by HIV-1 infection and involved in tumor progression, migration and invasion as a nuclear factor-κB (NF-κB)-dependent gene. The present study we intended to investigate the protein expression of AEG-1 significantly associated with rheumatoid arthritis. Western blot analysis and immunohistochemistry demonstrated that AEG-1 was upregulated in synovial tissue of RA patients compared with the controls. Double immunofluorescent staining suggested that AEG-1 was expressed in fibroblast-like synoviocytes (FLS) of RA patients. Furthermore, the expression of AEG-1 in FLS was increased in time-dependent manner by TNF-α stimulation. Upon TNF-α-treated FLS, AEG-1 transferred from the cytoplasm to nucleus where it interacted with the p65 subunit of NF-κB, as examined by immunoprecipitation and immunofluorescent staining assay. Moreover, the inhibition of AEG-1 by RNA interference significantly suppressed TNF-α-induced IL-6 and MMP-3 expression, leading to attenuation of FLS migration and invasion and markedly decreased the phosphorylation of P65 and IκBα, as well as AKT in FLS. Collectively, Our findings provided evidence that AEG-1 contributed to the production of inflammatory cytokines, migration and invasion of RA FLS, and underscored the importance of AEG-1 in the inflammation process of RA.     

Catabolic and anabolic periarticular bone changes in patients with rheumatoid arthritis: a computed tomography study on the role of age,disease duration and bone markers

Introduction

The aim of this study was to determine the factors, including markers of bone resorption and bone formation, which determine catabolic and anabolic periarticular bone changes in patients with rheumatoid arthritis (RA).

Methods

Forty RA patients received high-resolution peripheral quantitative computed tomography (HR-pQCT) analysis of the metacarpophalangeal joints II and III of the dominantly affected hand at two sequential time points (baseline, one year follow-up). Erosion counts and scores as well as osteophyte counts and scores were recorded. Simultaneously, serum markers of bone resorption (C-terminal telopeptide of type I collagen (CTX I), tartrate-resistant acid phosphatase 5b (TRAP5b)), bone formation (bone alkaline phosphatase (BAP), osteocalcin (OC)) and calcium homeostasis (parathyroid hormone (PTH), 25-hydroxyvitamin D3 (Vit D)) were assessed. Bone biomarkers were correlated to imaging data by partial correlation adjusting for various demographic and disease-specific parameters. Additionally, imaging data were analyzed by mixed linear model regression.

Results

Partial correlation analysis showed that TRAP5b levels correlate significantly with bone erosions, whereas BAP levels correlate with osteophytes at both time points. In the mixed linear model with erosions as the dependent variable, disease duration (P <0.001) was the key determinant for these catabolic bone changes. In contrast, BAP (P = 0.001) as well as age (P = 0.018), but not disease duration (P = 0.762), were the main determinants for the anabolic changes (osteophytes) of the periarticular bone in patients with RA.

Conclusions

This study shows that structural bone changes assessed with HR-pQCT are accompanied by alterations in systemic markers of bone resorption and bone formation. Besides, it can be shown that bone erosions in RA patients depend on disease duration, whereas osteophytes are associated with age as well as serum level of BAP. Therefore, these data not only suggest that different variables are involved in formation of bone erosions and osteophytes in RA patients, but also that periarticular bone changes correlate with alterations in systemic markers of bone metabolism, pointing out BAP as an important parameter.     

Development of selective inhibitors for the treatment of rheumatoid arthritis: (R)-3-(3-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor

A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib’s core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration. Compound 6 showed improved selectivity for JAK1 compared to that of tofacitinib (IC₅₀ 11, 2.4?×?10², 2.8?×?10³, and 1.1?×?10²?nM for JAK1, JAK2, JAK3, and TYK2, respectively). In CIA and AIA model tests, compound 6 exhibited similar efficacy to tofacitinib citrate.     

MTRX1011A,a humanized anti-CD4 monoclonal antibody,in the treatment of patients with rheumatoid arthritis: a Phase I randomized,double-blind,placebo-controlled study incorporating pharmacodynamic biomarker assessments

Introduction  

The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized anti-CD4 monoclonal antibody MTRX1011A in a randomized, double-blind placebo-controlled Phase 1 study in patients with rheumatoid arthritis (RA).     

Fatty acids uptake and oxidation are increased in the liver of rats with adjuvant-induced arthritis

Severe rheumatoid cachexia is associated with pronounced loss of muscle and fat mass in patients with advanced rheumatoid arthritis. This condition is associated with dyslipidemia and predisposition to cardiovascular diseases. Circulating levels of triglycerides (TG) and free fatty acids (FFA) have not yet been consistently defined in severe arthritis. Similarly, the metabolism of these lipids in the arthritic liver has not yet been clarified. Aiming at filling these gaps this study presents a characterization of the circulating lipid profile and of the fatty acids uptake and metabolism in perfused livers of rats with adjuvant-induced arthritis. The levels of TG and total cholesterol were reduced in both serum (10–20%) and liver (20–35%) of arthritic rats. The levels of circulating FFA were 40% higher in arthritic rats, possibly in consequence of cytokine-induced adipose tissue lipolysis. Hepatic uptake and oxidation of palmitic and oleic acids was higher in arthritic livers. The phenomenon results possibly from a more oxidized state of the arthritic liver. Indeed, NADPH/NADP⁺ and NADH/NAD⁺ ratios were 30% lower in arthritic livers, which additionally presented higher activities of the citric acid cycle driven by both endogenous and exogenous FFA. The lower levels of circulating and hepatic TG possibly are caused by an increased oxidation associated to a reduced synthesis of fatty acids in arthritic livers. These results reveal that the lipid hepatic metabolism in arthritic rats presents a strong catabolic tendency, a condition that should contribute to the marked cachexia described for arthritic rats and possibly for the severe rheumatoid arthritis.