CD200R is a member of the Ig supergene family that is primarily expressed on myeloid cells. Recent in vivo studies have suggested that CD200R is an inhibitory receptor capable of regulating the activation threshold of inflammatory immune responses. Here we provide definitive evidence that CD200R is expressed on mouse and human mast cells and that engagement of CD200R by agonist Abs or ligand results in a potent inhibition of mast cell degranulation and cytokine secretion responses. CD200R-mediated inhibition of FcεRI activation was observed both in vitro and in vivo and did not require the coligation of CD200R to FcεRI. Unlike the majority of myeloid inhibitory receptors, CD200R does not contain a phosphatase recruiting inhibitory motif (ITIM); therefore, we conclude that CD200R represents a novel and potent inhibitory receptor that can be targeted in vivo to regulate mast cell-dependent pathologies.

The controlled pyrolysis of mesoporous polysaccharide-derived materials, from starch and alginic acid, formed carbonaceous materials (Starbons 1 ) and were demonstrated as efficient materials for the removal of dyes from wastewater. The resulting materials were characterised by solid-state NMR, N 2 adsorption porosimetry, FT-IR, scanning electron microscopy (SEM) and tunnelling electron microscopy (TEM). The material's efficiency for dye adsorption was tested using methylene blue (MB) and acid blue 92 (AB) dyes. Adsorption data indicated that the mesoporosity of the material had a far greater influence on the adsorption capacity and speed of adsorption, than high surface area alone. Mesoporous Starbon 1 (A300) was evaluated against commercially available activated carbon (Norit) and demonstrated a superior adsorption capacity of MB; 186 mg g 21 vs. 42 mg g 21 . The kinetic activity of Starbon 1 was also determined with A800 showing the fastest rate of adsorption compared to S800 and Norit, suggesting that it is a more suitable material for water purification.

The binding of an anionic surfactant onto an anionic surface by addition of divalent ions is reported based on experimental data from specular neutron reflection (NR) and attenuated total internal reflection IR spectroscopy (ATR-IR). Similar measurements using monovalent ions (sodium) do not show any evidence of such adsorption, even though the amount of surfactant can be much higher. This data is interpreted in terms of the so-called bridging mechanism of ion binding.

c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non-small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML). Treatment with the small-molecule inhibitors imatinib, sunitinib, and regorafenib resulted in resistance (c-KIT mutant tumors) or limited activity (c-KIT wild-type tumors). We selected an anti-c-KIT ADC approach to evaluate the anticancer activity in multiple disease models. A humanized anti-c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a noncleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated against GIST, SCLC, and AML models and against GIST and SCLC models. LOP628 exhibited potent antiproliferative activity on c-KIT-positive cell lines, whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well tolerated in monkeys with an adequate therapeutic index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT-directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/lymphatic system. The preclinical findings suggest that the c-KIT-directed ADC may be a promising therapeutic for the treatment of mutant and wild-type c-KIT-positive cancers and supported the clinical evaluation of LOP628 in GIST, AML, and SCLC patients. .

SummaryThe Fc receptors (FcR), which belong to the immunoglobulin (Ig) superfamily, bind to specific Ig isotypes with varying affinities triggering complex immune defense responses. Several of the Fctk that lack signaling motifs in their cytoplasmic domains rely on associated subunits to transmit signals. Two classes of Fctk that bind the Fc portion oflgG, FcyRI, and FcytklIIa associate with a subunit shared among several FcR, the y chain, which is involved in receptor expression and signal transduction. In this report, we propose that a novel role for y chain is to enhance the affinity of Fcytk for ligand. Our findings demonstrate that FcytkI requires y-chain association to attain high affinity binding for monomeric IgG, and suggest that the intermediate binding affinity of the FcyIklIIa isoform results from its association with y chain. The affinity increase conferred by y chain appears to be mediated through the transmembrane domain of the Fcytk, with no requirement for the cytoplasmic domain of the receptor.