Fcγ receptor binding is required for maximal immunostimulation by CD70-Fc

Introduction: T cell expressed CD27 provides costimulation upon binding to inducible membrane expressed trimeric CD70 and is required for protective CD8 T cell responses. CD27 agonists could therefore be used to bolster cellular vaccines and anti-tumour immune responses. To date, clinical development of CD27 agonists has focussed on anti-CD27 antibodies with little attention given to alternative approaches. Methods: Here, we describe the generation and activity of soluble variants of CD70 that form either trimeric (t) or dimer-of-trimer proteins and conduct side-by-side comparisons with an agonist anti-CD27 antibody. To generate a dimer-of-trimer protein (dt), we fused three extracellular domains of CD70 to the Fc domain of mouse IgG1 in a ‘string of beads’ configuration (dtCD70-Fc). Results: Whereas tCD70 failed to costimulate CD8 T cells, both dtCD70-Fc and an agonist anti-CD27 antibody were capable of enhancing T cell proliferation in vitro. Initial studies demonstrated that dtCD70-Fc was less efficacious than anti-CD27 in boosting a CD8 T cell vaccine response in vivo, concomitant with rapid clearance of dtCD70-Fc from the circulation. The accelerated plasma clearance of dtCD70-Fc was not due to the lack of neonatal Fc receptor binding but was dependent on the large population of oligomannose type glycosylation. Enzymatic treatment to reduce the oligomannose-type glycans in dtCD70-Fc improved its half-life and significantly enhanced its T cell stimulatory activity in vivo surpassing that of anti-CD27 antibody. We also show that whereas the ability of the anti-CD27 to boost a vaccine response was abolished in Fc gamma receptor (FcγR)-deficient mice, dtCD70-Fc remained active. By comparing the activity of dtCD70-Fc with a variant (dtCD70-Fc(D265A)) that lacks binding to FcγRs, we unexpectedly found that FcγR binding to dtCD70-Fc was required for maximal boosting of a CD8 T cell response in vivo. Interestingly, both dtCD70-Fc and dtCD70-Fc(D265A) were effective in prolonging the survival of mice harbouring BCL1 B cell lymphoma, demonstrating that a substantial part of the stimulatory activity of dtCD70-Fc in this setting is retained in the absence of FcγR interaction. Discussion: These data reveal that TNFRSF ligands can be generated with a tunable activity profile and suggest that this class of immune agonists could have broad applications in immunotherapy

TREATMENT OF THE MARGINALIZED IN THE SELECT SHORT STORIES OF KHUSHWANT SINGH Dadas Anil N.

<p>As a prolific and India’s best-known writer, Khushwant Singh has multidimensional view towards life. When Khushwant Singh writes anything it attracts immediate attention and has also potential for tremendous impact, positive or negative. His genius as a writer has been recognized all over the world. He has touched almost all the forms of literature. He began his career as a short story writer and published The Mark of Vishnu and Other Stories in 1950. Khushwant Singh is also the best known for his novels. His masterpiece, Train to Pakistan (1956), was produced with a brilliant cast. It is necessary to analyze Khushwant Singh’s short stories to see either his female characters are marginalized or he has given them due credit to them. It is because marginalization or social exclusion is generally a curse to woman at individual level and society at public level which is a hindrance in the welfare of women. Mostly, the mindset of women is made to understand oppression and marginalization as a problem of system (male dominance) and not as the individual fault.</p

Retrospective climate resilience assessment of semi-arid farming systems in India

Semi-arid farming systems in India are facing an increasing frequency of climate change-induced extreme weather events. With the aim of improving their climate resilience, we retrospectively assess climate resilience in two case studies in Maharashtra, India. We considered a 15-year period and multiple interventions in both. The systems showed improved climate resilience when agricultural productivity-enhancing interventions were combined with those related to water management, soil health, livelihood diversification, and food and nutrition security. Further, we recommend embedding a monitoring, evaluation and learning component within the design of all interventions to help with adaptive decision-making

Practical Applications of Hydrogel for Irrigation in Water Scarce Area

Water being most important and basic resource for crop production is always in high demand. The scarcity of water reflects upon photosynthesis, translocation, respiration utilization of minerals and cell division. Due to water deficiency, many draught prone areas and uneven rainfall in India, it is important to mitigate water losses and to increase efficient use of water for better yield of crops and vegetation. The water needs in India can be fulfilled in much greater potential by use of hydrogel and such super absorbent polymers. Hydrogel is a polymer which is cross linked structure. It can absorb up to 30-40 times of its weight in pure water and then forms gel granules. It increases the water holding capacity, water efficiency, and permeability. It helps in reducing the irrigation frequency, dry density, water runoff. It can be degraded by both living and non-living environment factors. Hence practical application of hydrogel is much important in drought prone areas

Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering

Agonistic CD27 monoclonal antibodies (mAb) have demonstrated impressive anti-tumour efficacy in multiple preclinical models but modest clinical responses. This might reflect current reagents delivering suboptimal CD27 agonism. Here, using a novel panel of CD27 mAb including a clinical candidate, we investigate the determinants of CD27 mAb agonism. Epitope mapping and in silico docking analysis show that mAb binding to membrane-distal and external-facing residues are stronger agonists. However, poor epitope-dependent agonism could partially be overcome by Fc-engineering, using mAb isotypes that promote receptor clustering, such as human immunoglobulin G1 (hIgG1, h1) with enhanced affinity to Fc gamma receptor (FcγR) IIb, or hIgG2 (h2). This study provides the critical knowledge required for the development of agonistic CD27 mAb that are potentially more clinically efficacious