First-in-Human Study in Healthy Subjects with the Noncytotoxic Monoclonal Antibody OSE-127, a Strict Antagonist of IL-7Rα.

OSE-127 is a humanized mAb targeting the IL-7Rα-chain (CD127), under development for inflammatory and autoimmune disease treatment. It is a strict antagonist of the IL-7R pathway, is not internalized by target cells, and is noncytotoxic. In this work, a first-in-human, phase I, randomized, double-blind, placebo-controlled, single-center study was carried out to determine the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of OSE-127 administration. Sixty-three healthy subjects were randomly assigned to nine groups: six single ascending dose groups with i.v. administration (0.002-10 mg/kg), a single s.c. treatment group (1 mg/kg), and two double i.v. injection groups (6 or 10 mg/kg). Subjects were followed during <146 d. OSE-127's pharmacokinetic half-life after a single dose increased from 4.6 (1 mg/kg) to 11.7 d (10 mg/kg) and, after a second dose, from 12.5 (6 mg/kg) to 16.25 d (10 mg/kg). Receptor occupancy was ≥95% at doses ≥0.02 mg/kg, and this saturation level was maintained >100 d after two i.v. infusions at 10 mg/kg. IL-7 consumption was inhibited by OSE-127 administration, as demonstrated by a decreased IL-7 pathway gene signature in peripheral blood cells and by ex vivo T lymphocyte restimulation experiments. OSE-127 was well tolerated, with no evidence of cytokine-release syndrome and no significant alteration of blood lymphocyte counts or subset populations. Altogether, the observed lack of significant lymphopenia or serious adverse events, concomitant with the dose-dependent inhibition of IL-7 consumption by target cells, highlights that OSE-127 may show clinical activity in IL-7R pathway-involved diseases.

Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance.

T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.

Influence of polysaccharide coating on the interactions of nanoparticles with biological systems.

Since dextran (DEX) grafted with poly(epsilon-caprolacton) (PCL) side chains (PCL-DEX) copolymers could form nanoparticles with a well defined core-shell structure, we investigated the ability of the DEX coating to modify the interactions with the biological media. We first studied the influence of the DEX coating on the phagocytosis of the nanoparticles by human TPH-1 and J774 murine macrophage-like cell lines. Then, the activation of the complement system (CH50 measurement) at the surface of the particles and the adsorption of plasma proteins (2D-PAGE) were investigated, too. It was found that the modification of the surface with DEX significantly reduced the cytotoxicity towards J774 macrophages: the IC50 was increased from 10 to 600 microg/ml. However, the DEX coating could activate complement, probably due to a loop-like conformation of DEX similar to that of cross-linked DEX in Sephadex (a strong complement activator). In addition, depending on whether the DEX loops were large or compact, preferential adsorption, apolipoproteins or immunoglobulins, was observed.

Novel polyester-polysaccharide nanoparticles.

PURPOSE: The aim of the present study was to develop a new type of core-shell nanoparticles from a family of novel amphiphilic copolymers, based on dextran (DEX) grafted with poly(epsilon-caprolactone) (PCL) side chains (PCL-DEX). METHODS: A family of PCL-DEX copolymers was synthesized in which both the molecular weight and the proportion by weight of DEX in the copolymer were varied. The nanoparticles were prepared by a technique derived from emulsion-solvent evaporation, during which emulsion stability was investigated using a Turbiscan. The nanoparticle size distribution, density, zeta potential, morphology, and suitability for freeze-drying were determined. RESULTS: Because of their strongly amphiphilic properties, the PCL-DEX copolymers were able to stabilize o/w emulsions without the need of additional surfactants. Nanoparticles with a controlled mean diameter ranging from 100 to 250 nm were successfully prepared. A mechanism of formation of these nanoparticles was proposed. Zeta potential measurements confirmed the presence of a DEX coating. CONCLUSION: A new generation of polysaccharide-decorated nanoparticles has been successfully prepared from a family of PCL-DEX amphiphilic copolymers. They may have potential applications in drug encapsulation and targeting.

Study of emulsion stabilization by graft copolymers using the optical analyzer Turbiscan.

Oil-in-water nanoemulsions were prepared using a series of synthetic graft copolymers with a backbone of dextran (DEX) and a number of side chains of poly-epsilon-caprolactone (PCL). In this paper, we focus on the o/w emulsion stabilizing abilities of these novel PCL-DEX copolymers, using a recently developed optical analyzer (Turbiscan). The main advantage of Turbiscan is to detect the destabilization phenomena in non-diluted emulsion, much earlier than the naked eye's operator, especially in the case of an opaque and concentrated system. This study shows that PCL-DEX copolymers successfully stabilized ethyl acetate-in-water emulsions, even in the absence of additional surfactants, whereas they were not efficient in stabilizing methylene chloride-in-water emulsions which coalesced fast and irreversibly. The ethyl acetate-in-water emulsion stabilizing ability of PCL-DEX seemed to be related to the localization of their blocks with regard to the oil-water interface.