FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells

Carrascosa, Lucia Campos; Beek, Adriaan A. van; Ruiter, Valeska de; Doukas, Michail; Wei, Jie; Fisher, Timothy S.; Ching, Keith A.; Yang, Wenjing; Loon, Karlijn van; Boor, Patrick P.C.; Rakké, Yannick S.; Noordam, Lisanne; Doornebosch, Pascal G.; Grünhagen, Dirk J.; Verhoef, Kees; Polak, Wojciech; IJzermans, Jan N.M.; Ni, Irene; Yeung, Yik Andy; Salek-Ardakani, Shahram; Sprengers, Dave; Kwekkeboom, Jaap

doi:10.1136/jitc-2020-000816

Cited by 13 publications

(20 citation statements)

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“…Targeting the membrane proximal domains appears optimal for both deletion and agonism; with the latter strongly driven by isotypes with low A:I ratios such as mIgG1. Lowering the A:I ratio can be attained in many different ways, for example, by increasing the affinity for FcγRIIB, which has been shown to mediate more effective agonism for anti-CD40 mAb 52 and a recent paper showed that this may also be true for OX40 using a clinically relevant antibody 53 in vitro but as yet it is unclear whether this will be true in vivo for anti-hOX40 mAb. These findings have implications for the design of the next generation of anti-hOX40 mAb for the clinic.…”

Section: Discussionmentioning

confidence: 99%

Domain binding and isotype dictate the activity of anti-human OX40 antibodies

Griffiths

Hussain

Smith

et al. 2020

J Immunother Cancer

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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.

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Section: Discussionmentioning

confidence: 99%

Domain binding and isotype dictate the activity of anti-human OX40 antibodies

Griffiths

Hussain

Smith

et al. 2020

J Immunother Cancer

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“…Publically available RNA-sequencing data (GSE152904; GSM4629190, GSM4629187, GSM4629184, and GSM4629181) were used for analysis of comprehensive cytokine expression profiles in human CD4+ T cells induced by OX40 signaling (GEO accession). CD4+ T cells were stimulated in vitro in the presence of anti-CD3/CD28 activation beads, with or without agonistic OX40 antibody for 3 to 5 days, after which RNAsequencing was performed to evaluate OX40-mediated transcriptional changes (34). Gene expression was quantified by RSEM (v1.2.14).…”

Section: Rna-sequencing Analysismentioning

confidence: 99%

Peripheral TIGIT+ T Follicular Helper Cells That Produce High Levels of Interleukin-21 via OX40 Represent Disease Activity in IgG4-Related Disease

et al. 2021

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ObjectivesMultiple studies suggest that interleukin (IL)-21 plays a pivotal role in the differentiation of B cells and activation of cytotoxic T cells and is involved in the pathogenesis of IgG4-related disease (IgG4-RD). T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a new marker of T follicular helper (Tfh) cells, yet its significance remains unknown. The objective of this study was to investigate whether TIGIT expression could detect high IL-21-producing peripheral Tfh populations and their association with disease activity in IgG4-RD.MethodsTIGIT expression in peripheral CD4+T cell subsets was comprehensively analyzed by multi-color flow cytometry. Single cell mapping was performed by t-SNE method, and IL-21 production was compared in TIGIT+ and TIGIT-T cells. The effect of OX40 signal on cytokine expression was analyzed by RNA-sequencing. Clinical significance of TIGIT+ and TIGIT- peripheral T cells was analyzed in active patients with IgG4-RD, both at baseline and after 12 weeks of glucocorticoid treatment.ResultsUnbiased single cell mapping revealed two high IL-21-producing peripheral T cell populations; TIGIT+ Tfh and TIGIT-T helper cells. OX40 signal was associated with high IL-21 production in TIGIT+ Tfh and TIGIT-T helper cells. IL-21 production in Tfh cells correlated with the proportion of TIGIT+ cells in Tfh cells, serum IgG4 level, and scores of disease activity. Furthermore, the skewing toward peripheral TIGIT+ Tfh cells, particularly TIGIT+Tfh2 subset correlated with disease activity and was corrected by glucocorticoid treatment in IgG4-RD.ConclusionsOX40 is associated with high IL-21 production in peripheral TIGIT+ Tfh cells, and the increase in peripheral TIGIT+ Tfh cells reflects disease activity in IgG4-RD.

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“…Platelet secretion of vascular endothelial growth factors, migration, and proliferation of endothelial cells have an induction effect, increased vascular permeability, tumor cell penetrating machine vascular metastasis, and invasive chances [ 12 , 13 ]. RDW reflects the heterogeneous parameters of red blood cell size and peripheral blood [ 14 , 15 ]. In addition, research shows that various factors will affect PLR and NLR individual test results and reduce sensitivity and specificity [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Value Research of NLR, PLR, and RDW in Prognostic Assessment of Patients with Colorectal Cancer

Chen

Shen

2022

Journal of Healthcare Engineering

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Objective. This study aimed to investigate the relevance of the study with the neutrophil count and lymphocyte count ratio (NLR), platelet count and lymphocyte count ratio (PLR), and red blood cell distribution width (RDW) in the prognostic evaluation of colorectal cancer patients. Methods. 143 patients with colorectal cancer from January 2016 to January 2019 were selected by our hospital, and then, other 143 cases of physical examiners as normal groups were selecting to proceed colonoscopic biopsy to diagnose 106 cases of precancerous diseases related to colorectal cancer. Among them were the inflammatory bowel group (n = 56) and the colorectal polyp group (n = 50). Analysis of the survival impact factors of patients with carcinoma of the rectum, preoperative NLR, ROW, PLR, and prognostic relationship, and comparison of NLR, PLR, and RDW diagnostic rate and expression were performed. Results. Tissue type, TNM stage, lymph node metastasis, NLR, RDW, and PLR had a predictive influence on patients with colorectal cancer ( P 0.05 ). There was no link between gender, age, aetiology, pathological type, and prognosis in patients with colorectal cancer ( P > 0.05 ). Multiple variables in patients with colorectal cancer are affected by tissue categorization (poor differentiation), TNM stages (III, IV), lymph node metastases, NLR, ROW, and PLR ( P 0.05 ). When compared to solo NLR, Row, and PLR diagnostics, the combination diagnosis and malignancy rates were greater, and the differences were statistically significant ( P 0.05 ). Diagnostic sensitivity, specificity, and accuracy were greater when compared to single NLR, ROW, and PLR. When compared to the normal control group, NLR, ROW, and PLR have greater levels, and the differences are statistically significant ( P 0.05 ). The patient survival declines more slowly as PLR, NLR, and the severity of the condition rises. Conclusion. NLR, ROW, and PLR combined diagnosis has high accuracy in colorectal cancer diagnosis, and the prognosis of patients with NLR, ROW, and PLR levels has a tight association; so, clinically, the above signs should be identified, and the optimal treatment time is grasped.

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FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells

Cited by 13 publications

References 50 publications

Domain binding and isotype dictate the activity of anti-human OX40 antibodies

Domain binding and isotype dictate the activity of anti-human OX40 antibodies

Peripheral TIGIT+ T Follicular Helper Cells That Produce High Levels of Interleukin-21 via OX40 Represent Disease Activity in IgG4-Related Disease

Value Research of NLR, PLR, and RDW in Prognostic Assessment of Patients with Colorectal Cancer

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