Discovery, development, and characterization of SPY002 and SPY072, two novel extended half-life monoclonal antibodies targeting TL1A: in vitro properties, in vivo pharmacology, pharmacokinetics, and preclinical safety

mAbs · 2026-05-10

≈ 31-35 pM) and potent functional inhibition of DR3 signaling. Based on Fc modifications, SPY002 and SPY072 showed attenuated Fc effector function and increased FcRn binding at acidic pH (5.8). Both antibodies exhibited enhanced PK profiles in nonhuman primates, resulting in predicted human half-lives that support quarterly or biannual dosing. In toxicity studies, no drug-related adverse effects were observed with either antibody at exposures >10 times those anticipated in clinical trials. In a rat collagen-induced arthritis model, anti-TL1A antibody treatment effectively reduced arthritis severity, with similar efficacy to the TNF antagonist etanercept. In humanized mouse Imiquimod-induced psoriasis and 2,4,6‑trinitrobenzene sulfonic acid colitis models, anti-TL1A demonstrated similar efficacy to anti-IL-23 and anti-TNF antibodies. These findings characterize two novel extended half-life TL1A antibodies and support the ongoing Phase 2 clinical development of SPY002 and SPY072 for immune-mediated diseases such as inflammatory bowel disease and rheumatic diseases.

3112 Cerebral inflammation secondary to polymer embolization following endovascular clot retrieval for ischaemic stroke in a young woman with autoimmune comorbidities

2024-08-01

with alpha-synucleinopathy, 46 with autoimmune autonomic disorders, and 194 with peripheral neuropathy.Results Of 642 patients, 477 had nOH on AST or HUT (74.3%).Of these, 8.6% were identified only on HUT and 4% only on AST.Delayed OH was identified in 8.5% of cases on AST and in 4.5% of cases on HUT.Delayed OH was more commonly identified in patients with peripheral neuropathy and less commonly seen in patients with AAD.Patients with dOH had lower supine blood pressure (BP), smaller drop in last BP, lower orthostatic intolerance ratio, and greater rise in noradrenaline levels on upright tilt.Conclusion HUT and AST are complementary techniques in the recognition of nOH in patients with autonomic failure.Prolonged orthostatic challenges are useful for the detection of dOH, which appears to reflect milder sympathetic dysfunction in patients with autonomic failure.

Deep Learning Models Capture Histological Disease Activity in Crohn’s Disease and Ulcerative Colitis with High Fidelity

Journal of Crohn s and Colitis · 2023-10-10 · 43 citations

BACKGROUND AND AIMS: Histological disease activity in inflammatory bowel disease [IBD] is associated with clinical outcomes and is an important endpoint in drug development. We developed deep learning models for automating histological assessments in IBD. METHODS: Histology images of intestinal mucosa from phase 2 and phase 3 clinical trials in Crohn's disease [CD] and ulcerative colitis [UC] were used to train artificial intelligence [AI] models to predict the Global Histology Activity Score [GHAS] for CD and Geboes histopathology score for UC. Three AI methods were compared. AI models were evaluated on held-back testing sets, and model predictions were compared against an expert central reader and five independent pathologists. RESULTS: The model based on multiple instance learning and the attention mechanism [SA-AbMILP] demonstrated the best performance among competing models. AI-modelled GHAS and Geboes subgrades matched central readings with moderate to substantial agreement, with accuracies ranging from 65% to 89%. Furthermore, the model was able to distinguish the presence and absence of pathology across four selected histological features, with accuracies for colon in both CD and UC ranging from 87% to 94% and for CD ileum ranging from 76% to 83%. For both CD and UC and across anatomical compartments [ileum and colon] in CD, comparable accuracies against central readings were found between the model-assigned scores and scores by an independent set of pathologists. CONCLUSIONS: Deep learning models based upon GHAS and Geboes scoring systems were effective at distinguishing between the presence and absence of IBD microscopic disease activity.

A temporal classifier predicts histopathology state and parses acute-chronic phasing in inflammatory bowel disease patients

Communications Biology · 2023-01-24 · 9 citations

Previous studies have conducted time course characterization of murine colitis models through transcriptional profiling of differential expression. We characterize the transcriptional landscape of acute and chronic models of dextran sodium sulfate (DSS) and adoptive transfer (AT) colitis to derive temporal gene expression and splicing signatures in blood and colonic tissue in order to capture dynamics of colitis remission and relapse. We identify sub networks of patient-derived causal networks that are enriched in these temporal signatures to distinguish acute and chronic disease components within the broader molecular landscape of IBD. The interaction between the DSS phenotype and chronological time-point naturally defines parsimonious temporal gene expression and splicing signatures associated with acute and chronic phases disease (as opposed to ordinary time-specific differential expression/splicing). We show these expression and splicing signatures are largely orthogonal, i.e. affect different genetic bodies, and that using machine learning, signatures are predictive of histopathological measures from both blood and intestinal data in murine colitis models as well as an independent cohort of IBD patients. Through access to longitudinal multi-scale profiling from disease tissue in IBD patient cohorts, we can apply this machine learning pipeline to generation of direct patient temporal multimodal regulatory signatures for prediction of histopathological outcomes.

103: MACHINE LEARNING IDENTIFIES A 14 GENE TRANSCRIPTIONAL SIGNATURE IN THE CYTOKINE-REGULATED TRANSCRIPTOME THAT PREDICTS RESPONSE TO USTEKINUMAB IN CROHN'S DISEASE

Gastroenterology · 2022-05-01

Biopsy and blood-based molecular biomarker of inflammation in IBD

Gut · 2022-09-15 · 115 citations

OBJECTIVE: IBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments. DESIGN: Transcriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn's disease, n=421 UC and 243 controls) in the Mount Sinai Crohn's and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts. RESULTS: bMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time. CONCLUSION: Transcriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.

Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy

Nature Communications · 2022-10-03 · 129 citations

Abstract The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-22 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2 + neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2 + neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention.

O32 The interleukin 22//neutrophil axis is associated with treatment resistance in ulcerative colitis

Oral Presentations · 2022-06-01

<h3>Introduction</h3> Interleukin (IL) 22 is a key cytokine involved in regulation of epithelial function and its role in IBD remains highly controversial. Some studies indicate a protective role in epithelial regeneration, whereas other studies imply a pro-inflammatory role. Insights are now needed to improve of understanding of the functional role of this important cytokine and how its expression might impact patients with ulcerative colitis (UC). In this study, we have probed the clinical and functional significance of IL-22 responsive transcriptional modules and causal networks in diseased tissue of over 500 UC patients and in preclinical models of colitis. <h3>Methods</h3> We mapped the transcriptional landscape of human colonic epithelial 3D mini-gut organoids in response to treatment with IL22, and other pro-inflammatory cytokines. We tested the clinical significance of the IL22-regulated transcriptome by probing whole colonic biopsies from 550 ulcerative colitis (UC) patients from UNIFI clinical trial programme (patients with UC treated with ustekinumab, an anti-IL12p40 antibody). The functional role of IL22 regulated biological pathways were evaluated in pre-clinical models of UC. <h3>Results</h3> IL-22 regulated pro-inflammatory biological pathways involved in microbial recognition, cancer and immune cell chemotaxis. IL-22 was an especially potent regulator of the CXC family chemokines CXCL1, CXCL2, CXCL5, CXCL6 and CXCL8, which are all powerful neutrophil-selective chemokines. There was a positive correlation between the IL-22 transcriptional programme and the histological severity of inflammation (r=0.49, p&lt;0.0001) and, in particular, neutrophil infiltration in lamina propria and the colonic epithelium of patients with UC. Patients with the greatest magnitude of enrichment for IL22-responisve transcripts in whole colonic biopsies sampled immediately prior to ustekinumab initiation was associated with failure to achieve mucosal healing (8%) in comparison with patients with low enrichment scores (25%, P=0.002) at week 8 following induction. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression was highly conserved across species and was dependent on JAK1/STAT3 signalling. In preclinical models of colitis, IL-22 induction of neutrophil-active chemokines was functionally and pathologically important in the recruitment of CXCR2⁺ neutrophils to the colon. <h3>Conclusions</h3> The interleukin 22/neutrophil axis is functionally important in colitis and is associated with treatment resistance in ulcerative colitis

Cytokine responsive networks in human colonic epithelial organoids unveil a molecular classification of inflammatory bowel disease

Cell Reports · 2022-09-01 · 40 citations

Interactions between the epithelium and the immune system are critical in the pathogenesis of inflammatory bowel disease (IBD). In this study, we mapped the transcriptional landscape of human colonic epithelial organoids in response to different cytokines responsible for mediating canonical mucosal immune responses. By profiling the transcriptome of human colonic organoids treated with the canonical cytokines interferon gamma, interleukin-13, -17A, and tumor necrosis factor alpha with next-generation sequencing, we unveil shared and distinct regulation patterns of epithelial function by different cytokines. An integrative analysis of cytokine responses in diseased tissue from patients with IBD (n = 1,009) reveals a molecular classification of mucosal inflammation defined by gradients of cytokine-responsive transcriptional signatures. Our systems biology approach detected signaling bottlenecks in cytokine-responsive networks and highlighted their translational potential as theragnostic targets in intestinal inflammation.

795: AN INTERLEUKIN 22/CHEMOKINE AXIS DRIVES COLONIC NEUTROPHIL RECRUITMENT AND TREATMENT RESISTANCE IN ULCERATIVE COLITIS

Gastroenterology · 2022-05-01