Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases

Anti-angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor-A (VEGF-A) have revolutionized treatment of retinal vascular diseases including age-related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti-VEGF-A monotherapy efficacy by targeting both VEGF-A and angiopoietin-2 (ANG-2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF-A. Simultaneous VEGF-A and ANG-2 inhibition was found to reduce vessel lesion number, permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain-exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF-A and ANG-2. RG7716 showed greater efficacy than anti-VEGF-A alone in a non-human primate laser-induced CNV model after intravitreal delivery. Modification of RG7716’s FcRn and FccR binding sites disabled the antibodies’ Fc-mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential nextgeneration therapy for neovascular indications of the eye

Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.

Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth

A Study of the reaction e+ e- ---> mu+ mu- around the Z0 pole

Contains fulltext : 129369.pdf (publisher's version ) (Open Access

SEARCH FOR THE t AND b-prime QUARKS IN HADRONIC DECAYS OF THE Z0 BOSON

We present a search for the third generation up type quark t and a possible fourth down type quark b' in hadronic Z0 decays observed in DELPHI at the LEP collider. For any scenario with a decay through the charged current or into a charged Higgs with a mass at least 6 GeV/c2 below the t and 3 GeVc2 below the b' mass, we set a lower limit for the t quark mass at 44.0 GeV/c2 and for the b' mass at 44.5 GeV/c2. For specific scenarios the mass limits are slightly higher, e.g. for charged current decays the limits are 44.5 and 45.0 GeV/c2 respectively, where all limits are given at a 95% confidence level. © 1990.0SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Search for scalar quarks in Z0 decays

A search has been made for pairs of scalar quarks (squarks) produced in e+e- annihilations at LEP (√s≃MZ0), and decaying into a standard quark and a neutral, non-interacting, stable, massive particle (the lightest supersymmetric particle, LSP). The search has been conducted for differences in the mass of the squark and LSP of 2 GeV/c2 and above. Up squarks with masses below 42 GeV/c2 and down squarks below 43 GeV/c2 were excluded. Six squark flavours degenerate in mass were excluded below 45 GeV/c2.0SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A Comparison of jet production rates on the Z0 resonance to perturbative QCD

The production rates for 2-, 3-, 4- and 5-jet hadronic final states have been measured with the DELPHI detector at the e+e- storage ring LEP at centre of mass energies around 91.5 GeV. Fully corrected data are compared to O(αs 2) QCD matrix element calculations and the QCD scale parameter ΛMS is determined for different parametrizations of the renormalization scale μ2. Including all uncertainties our result is αs(MZ 2)=0.114±0.003[stat.]±0.004[syst.]±0.012[theor.] .0SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A Search for sleptons and gauginos in Z0 decays

Using a data sample corresponding to 10 000 hadronic Z0 decays, we have searched for the production of sleptons and gauginos in the two-prong decays of Z0. No candidate remains after straightforward selections. For neutralinos, we use selection methods developed in our previous search for neutral Higgs particles. The negative results are translated into improved mass limits and parameter constraints on the minimal supersymmetric extension of the standard model