Overexpression of CD70 has been documented in a variety of solid and hematological tumors, where it is thought to play a role in tumor proliferation and evasion of immune surveillance. Here, we ...describe ARGX-110, a defucosylated IgG1 monoclonal antibody (mAb) that selectively targets and neutralizes CD70, the ligand of CD27.
ARGX-110 was generated by immunization of outbred llamas. The antibody was germlined to 95% human identity, and its anti-tumor efficacy was tested in several in vitro assays. ARGX-110 binds CD70 with picomolar affinity. In depletion studies, ARGX-110 lyses tumor cells with greater efficacy than its fucosylated version. In addition, ARGX-110 demonstrates strong complement-dependent cytotoxicity and antibody-dependent cellular phagocytosis activity. ARGX-110 inhibits signaling of CD27, which results in blocking of the activation and proliferation of Tregs. In a Raji xenograft model, administration of the fucosylated version of ARGX-110 resulted in a prolonged survival at doses of 0.1 mg/kg and above. The pharmacokinetics of ARGX-110 was tested in cynomolgus monkeys; the calculated half-life is 12 days.
In conclusion, ARGX-110 is a potent blocking mAb with a dual mode of action against both CD70-bearing tumor cells and CD70-dependent Tregs. This antibody is now in a Phase 1 study in patients with advanced malignancies expressing CD70 (NCT01813539).
Duchenne muscular dystrophy is characterized by structural degeneration of muscle, which is exacerbated by localized functional ischemia due to loss of nitric oxide synthase-induced vasodilation. ...Treatment strategies aimed at increasing vascular perfusion have been proposed. Toward this end, we have developed monoclonal antibodies (mAbs) that bind to the vascular endothelial growth factor (VEGF) receptor VEGFR-1 (Flt-1) and its soluble splice variant isoform (sFlt-1) leading to increased levels of free VEGF and proangiogenic signaling. The lead chimeric mAb, 21B3, had high affinity and specificity for both human and mouse sFlt-1 and inhibited VEGF binding to sFlt-1 in a competitive manner. Proof-of-concept studies in the mdx mouse model of Duchenne muscular dystrophy showed that intravenous administration of 21B3 led to elevated VEGF levels, increased vascularization and blood flow to muscles, and decreased fibrosis after 6–12 weeks of treatment. Greater muscle strength was also observed after 4 weeks of treatment. A humanized form of the mAb, 27H6, was engineered and demonstrated a comparable pharmacologic effect. Overall, administration of anti-Flt-1 mAbs in mdx mice inhibited the VEGF:Flt-1 interaction, promoted angiogenesis, and improved muscle function. These studies suggest a potential therapeutic benefit of Flt-1 inhibition for patients with Duchenne muscular dystrophy.
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Human-mouse cross-reactive monoclonal antibodies (mAbs) inhibiting the vascular endothelial growth factor (VEGF) receptor (Flt-1) with high affinity and specificity were developed. In the mdx mouse model of Duchenne muscular dystrophy (DMD), the mAbs increased VEGF levels, vascularization, and muscle function and decreased fibrosis, suggesting potential therapeutic benefit for DMD.
Activation of the classical and lectin pathway of complement may contribute to tissue damage and organ dysfunction of antibody-mediated diseases and ischemia-reperfusion conditions. Complement ...factors are being considered as targets for therapeutic intervention.
We sought to characterize ARGX-117, a humanized inhibitory monoclonal antibody against complement C2.
The mode-of-action and binding characteristics of ARGX-117 were investigated in detail. Furthermore, its efficacy was analyzed in in vitro complement cytotoxicity assays. Finally, a pharmacokinetic/pharmacodynamic study was conducted in cynomolgus monkeys.
Through binding to the Sushi-2 domain of C2, ARGX-117 prevents the formation of the C3 proconvertase and inhibits classical and lectin pathway activation upstream of C3 activation. As ARGX-117 does not inhibit the alternative pathway, it is expected not to affect the antimicrobial activity of this complement pathway. ARGX-117 prevents complement-mediated cytotoxicity in in vitro models for autoimmune hemolytic anemia and antibody-mediated rejection of organ transplants. ARGX-117 exhibits pH- and calcium-dependent target binding and is Fc-engineered to increase affinity at acidic pH to the neonatal Fc receptor, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A 2-dose regimen of 80 and 20 mg/kg separated by a week, resulted in profound reduction of classical pathway activity lasting for at least 7 weeks.
ARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathways while leaving the alternative pathway intact.
Data‐independent acquisition (DIA) generates comprehensive yet complex mass spectrometric data, which imposes the use of data‐dependent acquisition (DDA) libraries for deep peptide‐centric detection. ...Here, it is shown that DIA can be redeemed from this dependency by combining predicted fragment intensities and retention times with narrow window DIA. This eliminates variation in library building and omits stochastic sampling, finally making the DIA workflow fully deterministic. Especially for clinical proteomics, this has the potential to facilitate inter‐laboratory comparison.
DOI: 10.1002/pmic.201900306
In article number 1900306, Van Puyvelde et al. present a unified graphic called the DIAmond DIAgram which the authors use to sample the currently‐available peptide‐centric ...DIA data analysis strategies and assess their performance. This leads them to an innovative and easily adoptable approach based on predicted spectral information and narrow window DIA. Their contribution removes the current need for DDA prior to DIA analysis, facilitating inter‐laboratory comparison, especially for clinical proteomics.
The point prevalence survey of healthcare-associated infections (HAIs) and antimicrobial use organized by the European Centre for Disease Prevention and Control (ECDC-PPS) and the Global Point ...Prevalence Survey of antimicrobial consumption (Global-PPS) were simultaneously performed in Belgian acute care hospitals in 2017.
Belgian acute care hospitals were invited to participate in either the ECDC or Global-PPS. Hospital/ward/patient-level data were collected between September-December 2017. All patients present in the wards at 8 a.m. on the day of the PPS were included. The data of the ECDC and Global-PPS on antimicrobial consumption were pooled. Detailed data on HAIs were analysed for ECDC-PPS.
Overall, 110 Belgian acute care hospital sites participated in the ECDC and Global-PPS (countrywide participation rate: 81.4%, 28,007 patients). Overall, a crude prevalence of patients with at least one antimicrobial of 27.1% (95% confidence interval (CI) 26.5-27.6%) was found. The most frequently reported indications were pneumonia (23.2%), urinary tract infections (15.2%) and skin and soft tissue infections (11.9%). The reason for antimicrobial use was recorded for 81.9% of the prescriptions, a stop/review date for 40.8% and compliance with local antibiotic guidelines for 76.6%. In the ECDC-PPS, the crude prevalence of patients with at least one HAI was 7.3% (95%CI 6.8-7.7%). Most frequently reported HAIs were pneumonia (21.6%) and urinary tract infections (21.3%).
HAI and antimicrobial use prevalence remained stable in comparison with the previous PPS (7.1% and 27.4% in 2011 and 2015, respectively). Belgian hospitals should be further stimulated to set local targets to improve antibiotic prescribing and reduce HAI.
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