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Antibody responses during infection and vaccination typically undergo affinity maturation to achieve high-affinity binding for efficient neutralization of pathogens 1 , 2 . Similarly, high affinity is routinely the goal for therapeutic antibody generation. However, in contrast to naturally occurring or direct-targeting therapeutic antibodies, immunomodulatory antibodies, which are designed to modulate receptor signalling, have not been widely examined for their affinity–function relationship. Here we examine three separate immunologically important receptors spanning two receptor superfamilies: CD40, 4-1BB and PD-1. We show that low rather than high affinity delivers greater activity through increased clustering. This approach delivered higher immune cell activation, in vivo T cell expansion and antitumour activity in the case of CD40. Moreover, an inert anti-4-1BB monoclonal antibody was transformed into an agonist. Low-affinity variants of the clinically important antagonistic anti-PD-1 monoclonal antibody nivolumab also mediated more potent signalling and affected T cell activation. These findings reveal a new paradigm for augmenting agonism across diverse receptor families and shed light on the mechanism of antibody-mediated receptor signalling. Such affinity engineering offers a rational, efficient and highly tuneable solution to deliver antibody-mediated receptor activity across a range of potencies suitable for translation to the treatment of human disease. In contrast to direct-targeting monoclonal antibodies, low affinity confers agonistic monoclonal antibodies with more potency.

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. 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). Whereas tCD70 failed to costimulate CD8 T cells, both dtCD70-Fc and an agonist anti-CD27 antibody were capable of enhancing T cell proliferation . Initial studies demonstrated that dtCD70-Fc was less efficacious than anti-CD27 in boosting a CD8 T cell vaccine response , 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 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 . 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. 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.

BackgroundDespite extensive clinical use, the mechanisms that lead to therapeutic resistance to anti-programmed cell-death (PD)-1 monoclonal antibodies (mAbs) remain elusive. Here, we sought to determine how interactions between the Fc region of anti-PD-1 mAbs and Fcγ receptors (FcγRs) affect therapeutic activity and how these are impacted by the immune environment.MethodsMouse and human anti-PD-1 mAbs with different Fc binding profiles were generated and characterized in vitro. The ability of these mAbs to elicit T-cell responses in vivo was first assessed in a vaccination setting using the model antigen ovalbumin. The antitumor activity of anti-PD-1 mAbs was investigated in the context of immune ‘hot’ MC38 versus ‘cold’ neuroblastoma tumor models, and flow cytometry performed to assess immune infiltration.ResultsEngagement of activating FcγRs by anti-PD-1 mAbs led to depletion of activated CD8 T cells in vitro and in vivo, abrogating therapeutic activity. Importantly, the extent of this Fc-mediated modulation was determined by the surrounding immune environment. Low FcγR-engaging mouse anti-PD-1 isotypes, which are frequently used as surrogates for human mAbs, were unable to expand ovalbumin-reactive CD8 T cells, in contrast to Fc-null mAbs. These results were recapitulated in mice expressing human FcγRs, in which clinically relevant hIgG4 anti-PD-1 led to reduced endogenous expansion of CD8 T cells compared with its engineered Fc-null counterpart. In the context of an immunologically ‘hot’ tumor however, both low-engaging and Fc-null mAbs induced long-term antitumor immunity in MC38-bearing mice. Finally, a similar anti-PD-1 isotype hierarchy was demonstrated in the less responsive ‘cold’ 9464D neuroblastoma model, where the most effective mAbs were able to delay tumor growth but could not induce long-term protection.ConclusionsOur data collectively support a critical role for Fc:FcγR interactions in inhibiting immune responses to both mouse and human anti-PD-1 mAbs, and highlight the context-dependent effect that anti-PD-1 mAb isotypes can have on T-cell responses. We propose that engineering of Fc-null anti-PD-1 mAbs would prevent FcγR-mediated resistance in vivo and allow maximal T-cell stimulation independent of the immunological environment.

Monoclonal antibodies (mAb) and natural ligands targeting costimulatory tumor necrosis factor receptors (TNFR) exhibit a wide range of agonistic activities and antitumor responses. The mechanisms underlying these differential agonistic activities remain poorly understood. Here, we employ a panel of experimental and clinically-relevant molecules targeting human CD40, 4-1BB and OX40 to examine this issue. Confocal and STORM microscopy reveal that strongly agonistic reagents induce clusters characterized by small area and high receptor density. Using antibody pairs differing only in isotype we show that hIgG2 confers significantly more receptor clustering than hIgG1 across all three receptors, explaining its greater agonistic activity, with receptor clustering shielding the receptor-agonist complex from further molecular access. Nevertheless, discrete receptor clustering patterns are observed with different hIgG2 mAb, with a unique rod-shaped assembly observed with the most agonistic mAb. These findings dispel the notion that larger receptor clusters elicit greater agonism, and instead point to receptor density and subsequent super-structure as key determinants.Yu et al examined a panel of both experimental and clinically-relevant TNF agonists in order to advance our understanding of the mechanisms underlying their varying activities and anti-tumor responses. They demonstrated that agonists with greater activity induced higher density receptor clustering and specific super-structures as opposed to simply larger receptor clusters.

BackgroundPrevious data suggests that anti-OX40 mAb can elicit anti-tumor effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. Human trials with anti-OX40 antibodies have shown that these entities are well tolerated but to date have delivered disappointing clinical responses, indicating that the rules for the optimal use of anti-human OX40 (hOX40) antibodies is not yet fully understood. Changes to timing and dosages may lead to improved outcomes; however, here we focus on addressing the role of agonism versus depleting activity in determining therapeutic outcomes. We investigated a novel panel of anti-hOX40 mAb to understand how these reagents and mechanisms may be optimized for therapeutic benefit.MethodsThis study examines the binding activity and in vitro activity of a panel of anti-hOX40 antibodies. They were further evaluated in several in vivo models to address how isotype and epitope determine mechanism of action and efficacy of anti-hOX40 mAb.ResultsBinding analysis revealed the antibodies to be high affinity, with epitopes spanning all four cysteine-rich domains of the OX40 extracellular domain. In vivo analysis showed that their activities relate directly to two key properties: (1) isotype—with mIgG1 mAb evoking receptor agonism and CD8+ T-cell expansion and mIgG2a mAb evoking deletion of Treg and (2) epitope—with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumor models by engaging these different mechanisms.ConclusionThese findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T-cell expansion or Treg depletion might be preferred according to the composition of different tumors. As many of the current clinical trials using OX40 antibodies are now using combination therapies, this understanding of how to manipulate therapeutic activity will be vital in directing new combinations that are more likely to improve efficacy and clinical outcomes.

It's never a good idea to be overlyrelient on technology while traveling! Look up words quickly and easily with this great travel-sized Korean dictionary.Intended for use by tourists, students, and business people traveling to Korea Pocket Korean Dictionary is an essential tool for communication and a great way to learn Korean. It features all the essential Korean vocabulary appropriate for beginning to intermediate students. It's handy pocket format and easy-to read type will make any future trip to Korea much easier.In addition to being an excellent English to Korean dictionary and Korean to English dictionary Pocket Korean Dictionary contains important notes on the Korean language, Korean grammar and Korean pronunciation. All Korean words are written in English as well as Korean script (hangul) so that in the case of difficulties the book can simply be shown to the person the user is trying to communicate with.This dictionary contains: The 11,000 most commonly used words and expressions in the Korean language. EnglishKorean and KoreanEnglish sections. Hangul and Romanized Korean. An introduction to and history of the Korean language. Designed for English speakers Information on Korean grammar. A guide to pronouncing Korean correctly.Other books from this bestselling series you might enjoy are: Pocket Tagalog Dictionary, Pocket Vietnamese Dictionary, Pocket Mandarin Chinese Dictionary, Pocket Cantonese Dictionary, Pocket Cambodian Dictionary, Pocket Indonesian Dictionary, Pocket Thai Dictionary, and Pocket Malay Dictionary.

B7 delivers a costimulatory signal through CD28, resulting in interleukin-2 secretion and T cell proliferation. Blockade of this pathway results in T cell anergy. The in vivo role of B7 was evaluated with B7-deficient mice. These mice had a 70 percent decrease in costimulation of the response to alloantigen. Despite lacking B7 expression, activated B cells from these mice bound CTLA-4 and GL1 monoclonal antibody, demonstrating that alternative CTLA-4 ligand or ligands exist. These receptors are functionally important because the residual allogenic mixed lymphocyte responses were blocked by CTLA4Ig. Characterization of these CTLA-4 ligands should lead to strategies for manipulating the immune response.

Alarming K-12 nationwide teacher attrition statistics have led reform efforts to focus on teacher retention (Olsen & Anderson, 2007), especially in urban schools where teacher burnout and attrition are high (Darling-Hammond, 1998). It was not until recently, however, that teacher resiliency, a strengths based framework (Henderson & Milstein, 2003), was viewed as an alternate lens of reform in achieving higher teacher retention. This study utilized a Likert survey to quantify if 284 elementary teachers in sixteen, public urban elementary schools in two urban school districts in southern California agree or disagree with the six most significant school factors linked to teacher resiliency. The six school factors known as collegiality/ collaboration, professional development, leadership, shared power, commitment to students, and teacher efficacy were identified by synthesizing the current literature on teacher resiliency and retention. The two most significant predictors of teacher resiliency from the literature, as found by multiple regression analyses, were commitment and values and shared power. This study also investigated whether resilient elementary teachers in urban schools self-reported any additional school factors linked to teacher resiliency, not originally identified in the literature. The significant additional school factors found in this study linked to resiliency were urban school dynamics, intrinsic motivation, and community.

Suppressor of Fused (SuFu) is an intracellular mediator of the Hedgehog signaling pathway with diverse biological roles, including a tumour suppressor function. Recent data suggest an essential role for this gene in cell differentiation in various tissues and cancers. Despite its known role as a tumour suppressor in medulloblastoma, a neuroectodermal tumour of cerebellar origin, the functional importance of SuFu in the developing cerebellum remains unknown. In this thesis, using in vivo conditional knockout approaches and in vitro assays, I present evidence for a novel requirement for SuFu during mid-hindbrain specification, cerebellar patterning and cell differentiation. (Abstract shortened by UMI.)

Previous data suggests that anti-OX40 mAb can elicit anti-tumour effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. The contributions of these different effector mechanisms has not previously been systematically evaluated, particularly for mAb directed to human OX40. Therefore, we generated a novel human OX40 knock-in (KI) mouse to evaluate a panel of anti-hOX40 mAb and show that their activities relate directly to two key properties: 1) isotype; with mIgG1 mAb evoking receptor agonism and CD8+ T cell expansion and mIgG2a mAb evoking deletion of Treg and; 2) epitope; with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumour models by engaging these different mechanisms. These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T cell expansion or Treg depletion might be preferable according to the composition of different tumours. Competing Interest Statement MSC is a retained consultant for BioInvent International and has performed educational and advisory roles for Baxalta and Boehringer Ingleheim. He has received research funding from Roche, Gilead, Bioinvent International and GSK. BF, IT, LM and MS are employees of Bioinvent International.