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TNF blockers are highly efficacious at dampening inflammation and reducing symptoms in rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and also in nonrheumatic syndromes such as inflammatory bowel disease. As TNF belongs to a superfamily of 19 structurally related proteins that have both proinflammatory and anti-inflammatory activity, reagents that disrupt the interaction between proinflammatory TNF family cytokines and their receptors, or agonize the anti-inflammatory receptors, are being considered for the treatment of rheumatic diseases. Biologic agents that block B cell activating factor (BAFF) and receptor activator of nuclear factor-κB ligand (RANKL) have been approved for the treatment of systemic lupus erythematosus and osteoporosis, respectively. In this Review, we focus on additional members of the TNF superfamily that could be relevant for the pathogenesis of rheumatic disease, including those that can strongly promote activity of immune cells or increase activity of tissue cells, as well as those that promote death pathways and might limit inflammation. We examine preclinical mouse and human data linking these molecules to the control of damage in the joints, muscle, bone or other tissues, and discuss their potential as targets for future therapy of rheumatic diseases.

IntroductionAngiopoietin-2 (Ang2) is a secreted ligand whose concentration is increased in several cardiovascular diseases, and which causes vascular inflammation, microvessel disintegration, cardiac fibrosis and myocardial damage. Ang2 binds the endothelial receptor Tie2, where it competes for binding with the protective ligand Ang1. In this study we aim to develop a ligand-trap to block Ang2 action. To do this we used directed protein evolution to change the binding specificity of the Tie2 ectodomain so that it specifically binds Ang2. The evolved ectodomain will then be used as a soluble trap for introduction into the circulation to bind and sequester Ang2 preventing it from exerting its effects on the endothelium.Methods and resultsTie2 ectodomain was evolved using a novel DT40 cell surface display and evolution system. Evolutions were performed for selective binding to Ang2 by iterative cycles of mutation and selection. Variants evolved for Ang2 binding were then sequenced revealing key residues in the Ang1/2 binding domain determining ligand specificity. Fusion proteins containing the evolved variants were expressed, purified and tested for their ability to selectively bind Ang2, rather than Ang1 and Ang4. These Ang2-selective ligand-traps were found to inhibit Ang2 action on endothelial cells, inhibit adhesion of platelet/leucocyte aggregates to endothelial monolayers and suppress LPS-induced oedema.Conclusions and implicationsUsing a novel method of cell surface display and directed evolution we have evolved Tie2 ectodomain to selectively bind Ang2. This has revealed the key amino acid residues determining ligand-binding specificity of Tie2. In addition we created a series of selective Ang2 ligand-traps. These traps are almost identical to the endogenous receptor ectodomain, differing in four or fewer amino acid residues from endogenous ectodomain, and are able to inhibit the actions of Ang2. These ligand-traps have the potential for development as therapeutics to block the pathogenic and inflammatory actions of Ang2 on the cardiovascular system.

BRATIONALE Programmed death 1 (PD-1) inhibitors are group of new drugs proved efficacy in many kinds of cancer including non-small cell lung cancer. According to predominant histology was 1 out of 2 (50.0%) in signet ring, 2 out of 12 (16.7%) in lepidic mucinous, 9 out of 60 (15.0%) in acinar, 3 out of 31 (9.7%) in solid, 4 out of 51 (7.8%) in nonmucinous lepidic, 1 out of 35 (2.9%) in papillary, none of 3 (0%) in micropapillary, and none of 1 (0%) in fetal were PD-L1 postive.

BackgroundThe programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors are increasingly studied and are known to have unique inflammatory side effects due to non-specific immune system activation.1 While rare, PD-1/PD-L1 inhibitors can cause ocular toxicities, including inflammatory eye disease.2 However, these ocular adverse events are less well-studied.MethodsThis was a retrospective review of two adverse event (AE) monitoring databases maintained by the National Cancer Institute’s Cancer Therapy Evaluation Program (CTEP), one of the largest public sponsors of clinical trials worldwide. One database (CTEP-AERS) is used for study sites to expeditiously report serious AEs for potential FDA review, while the other database (CDUS) is updated quarterly to reflect all the adverse events from the Phase 1 and Phase 2 trials in the CTEP network.ResultsThe two adverse event databases were queried for ocular adverse events up to May 19, 2020. A total of 331 adverse events from 259 patients were found. 73 patients (28%) were exposed to nivolumab, 117 patients (45%) were exposed to combination nivolumab and ipilimumab, 41 (16%) were exposed to pembrolizumab, 26 (10%) were exposed to atezolizumab, and 2 (0.8%) were exposed to durvalumab. 59 adverse events from 47 patients were reported by the study site as serious AEs and had more detailed clinical information available. Ocular AEs occurred within several months of initiating the study treatment (all ocular AEs: median 6 weeks, IQR 0–18, ocular AEs reported as serious: median 12 weeks, IQR 6–20). CTCAE grade for ocular AEs was generally mild to moderate (all ocular AEs: grade 1, IQR 1-2, ocular AEs reported as serious: grade 2, IQR 2-3). Clinical workup and treatment varied for the ocular AEs reported as serious. 30/47 patients (64%) receiving ophthalmologic evaluation.16/47 (34%) of patients with serious ocular AEs had to delay or discontinue study drug treatment. However, 14/47 (30%) had improvement in their ocular AE and 16/47 patients (34%) had resolution of their ocular AE. The most common ocular AE treatments in our dataset were steroids (intravenous, oral, and steroid eye drops).ConclusionsOcular adverse events are rare complications of PD-1/PD-L1 inhibitor therapy, can be severe enough to cause PD-1/PD-L1 treatment discontinuation or delay, but patients may not always be referred to eye specialists. Future PD-1/PD-L1 inhibitor studies would benefit from standardized plans for ophthalmologic evaluation of ocular toxicities.ReferencesPostow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. Longo DL, ed. N Engl J Med. 2018;378(2):158–168.Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. Checkpoint inhibitor immune therapy. Retina 2018;38(6):1063–1078.

Tumor necrosis-factor related apoptosis-inducing ligand, also known as TRAIL or APO2L (Apo-2 ligand), is a cytokine of the TNF superfamily acknowledged for its ability to trigger selective apoptosis in tumor cells while being relatively safe towards normal cells. Its binding to its cognate agonist receptors, namely death receptor 4 (DR4) and/or DR5, can induce the formation of a membrane-bound macromolecular complex, coined DISC (death-signaling inducing complex), necessary and sufficient to engage the apoptotic machinery. At the very proximal level, TRAIL DISC formation and activation of apoptosis is regulated both by antagonist receptors and by glycosylation. Remarkably, though, despite the fact that all membrane-bound TRAIL receptors harbor putative glycosylation sites, only pro-apoptotic signaling through DR4 and DR5 has, so far, been found to be regulated by - and -glycosylation, respectively. Because putative -glycosylation sequons and -glycosylation sites are also found and conserved in all these receptors throughout all animal species (in which these receptors have been identified), glycosylation is likely to play a more prominent role than anticipated in regulating receptor/receptor interactions or trafficking, ultimately defining cell fate through TRAIL stimulation. This review aims to present and discuss these emerging concepts, the comprehension of which is likely to lead to innovative anticancer therapies.

APO2L/TRAIL (TNF-related apoptosis-inducing ligand) induces death of tumor cells through two agonist receptors, TRAIL-R1 and TRAIL-R2. We demonstrate here that N-linked glycosylation (N-glyc) plays also an important regulatory role for TRAIL-R1-mediated and mouse TRAIL receptor (mTRAIL-R)-mediated apoptosis, but not for TRAIL-R2, which is devoid of N-glycans. Cells expressing N-glyc-defective mutants of TRAIL-R1 and mouse TRAIL-R were less sensitive to TRAIL than their wild-type counterparts. Defective apoptotic signaling by N-glyc-deficient TRAIL receptors was associated with lower TRAIL receptor aggregation and reduced DISC formation, but not with reduced TRAIL-binding affinity. Our results also indicate that TRAIL receptor N-glyc impacts immune evasion strategies. The cytomegalovirus (CMV) UL141 protein, which restricts cell-surface expression of human TRAIL death receptors, binds with significant higher affinity TRAIL-R1 lacking N-glyc, suggesting that this sugar modification may have evolved as a counterstrategy to prevent receptor inhibition by UL141. Altogether our findings demonstrate that N-glyc of TRAIL-R1 promotes TRAIL signaling and restricts virus-mediated inhibition.

Receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL) binds RANK on the surface of osteoclast precursors to trigger osteoclastogenesis. Recent studies have indicated that osteocytic RANKL has an important role in osteoclastogenesis during bone remodelling; however, the role of osteoblastic RANKL remains unclear. Here we show that vesicular RANK, which is secreted from the maturing osteoclasts, binds osteoblastic RANKL and promotes bone formation by triggering RANKL reverse signalling, which activates Runt-related transcription factor 2 (Runx2). The proline-rich motif in the RANKL cytoplasmic tail is required for reverse signalling, and a RANKL(Pro29Ala) point mutation reduces activation of the reverse signalling pathway. The coupling of bone resorption and formation is disrupted in RANKL(Pro29Ala) mutant mice, indicating that osteoblastic RANKL functions as a coupling signal acceptor that recognizes vesicular RANK. RANKL reverse signalling is therefore a potential pharmacological target for avoiding the reduced bone formation associated with inhibition of osteoclastogenesis.

An unconstrained two-tissue compartment modeling method was used to model these TACs and obtain estimates of VT, the ratio of the regional concentration of ligand to that in plasma at equilibrium. Since this type of systematic increase was not observed in [11C]ABP688 baboon test-retest studies (nor in human studies performed in our group using several other ligands), it is possible that [11C]ABP688 binding increases were due to physiological changes.