Proteomics-Driven Multiomic Studies Reveal Novel Drug Targets and Repurposing Opportunities Across Cardiovascular, Psychiatric, and Autoimmune Diseases
核心洞察
Multiomic profiling of atherosclerotic plaques and peripheral circulation identified 15 proteins linked to disease symptomatology, including novel markers PCOLCE, FUT5, and ICOSLG, with ANGPTL3 (搜索) tied to adverse cardiac events.
Researchers at Mount Sinai discovered shared Th2 protein dysregulation among major depressive disorder (搜索), psoriasis (搜索), and atopic dermatitis (搜索), suggesting dupilumab could be repurposed for MDD via an in silico druggability approach.
Cartesian Therapeutics' phase 2b trial of Descartes-08, an mRNA CAR-T cell therapy for myasthenia gravis (搜索), demonstrated precision immune reset without unwanted inflammation, with durable reductions in IL-6, CCL19, and other autoimmune markers.
The pharmaceutical industry is increasingly turning to high-throughput proteomic platforms to unlock novel drug targets, stratify patient populations, and uncover repurposing opportunities. A series of recent studies, leveraging Olink's Proximity Extension Assay (PEA) technology, demonstrates how proteomics-driven insights are reshaping drug development across cardiovascular disease, neuropsychiatric disorders, autoimmune conditions, and diabetic kidney disease.
"Traditionally, biomarker discovery was limited to analyzing one marker at a time, which constrained exploratory work and narrowed our view of disease biology," said Magnus Althage, PhD, Head of Translational Science Strategy at AstraZeneca R&D. "But with the advent of high-throughput proteomic platforms—capable of measuring thousands of proteins from just a small sample volume—we've unlocked the ability to explore the proteome at scale."
Multiomic Profiling Identifies Atherosclerotic Instability Signatures
Atherosclerotic cardiovascular disease (ASCVD (搜索)) remains a significant global health issue linked to high morbidity and mortality from ischemic stroke and myocardial infarction. Patients with unstable, symptomatic ASCVD face a more than 10-fold higher annual risk of stroke than those with stable, asymptomatic disease.
Scientists from Novo Nordisk A/S in Denmark and the Karolinska Institute in Stockholm integrated multiomic data acquired locally from atherosclerotic plaques and from the peripheral circulation of carotid stenosis patients. The researchers combined metabolomics, transcriptomics, and proteomics measured using five Olink Target 96 panels, employing the DIABLO machine learning method to derive molecular signatures associated with cardiovascular outcomes, plaque stability, and therapeutic responses.
The proteomic analysis identified 15 proteins closely linked to atherosclerotic disease symptomatology, overlapping in plasma taken from locations adjacent to plaque lesions and from peripheral circulation. Both well-established atherosclerosis markers and novel proteins were identified, including PCOLCE, FUT5, ICOSLG, CCL20, CA6, and KITLG.
Pathway analysis revealed that necroptosis, inflammation, coagulation, and cholesterol metabolism were key determinants of symptomatology. Notably, higher peripheral plasma protein levels of ANGPTL3 (搜索) were closely linked to more frequent significant adverse cardiac events and all-cause mortality. Testing of prioritized targets against the OpenTargets platform showed good evidence for the genetic involvement of F11, EGFR, IL6, C1S, and ANGPTL3 in cardiovascular diseases.
A 2026 commentary summarized the impact: "The targets presented here could have paradigm-shifting implications, especially for enabling tailored therapies and precision medicine in the fight against carotid atherosclerosis."
Proteomics Opens Door to Drug Repurposing in Psychiatry
Major depressive disorder (搜索) (MDD) affects more than 250 million people globally and represents a significant healthcare and economic burden. Evidence suggests that a subset of MDD patients exhibit a dysregulated immune system, hinting at pathophysiological overlaps with apparently unrelated diseases.
Researchers from the Icahn School of Medicine at Mount Sinai investigated whether MDD patients' proteomic profiles resemble those of patients with the inflammatory skin diseases psoriasis (搜索) (PS) and atopic dermatitis (搜索) (AD). Using multiple Olink Target 96 panels, the team identified a set of proteins dysregulated across all three patient groups, including TNFSF14, CCL13, CCL17, CXCL9, CXCL10, CXCL11, and CD40LG. Pathway analysis confirmed shared enrichment indicative of Th2 up-regulation across the three diseases.
The anti-IL-4Rα (搜索) monoclonal antibody dupilumab, commonly used to treat AD, emerged as a potential repurposing candidate through in silico druggability analysis. Published clinical trial data showed that several Th2 proteins shared between MDD and AD were influenced by dupilumab. Furthermore, a mouse model of psychosocial stress revealed that inhibition of IL-4Rα lowered stress-induced behaviors.
"The back-translational drug repurposing strategy employed in this study may offer a novel approach to identify immunomodulatory drugs in psychiatry," the authors noted.
mRNA CAR-T Cell Therapy Demonstrates Precision Immune Reset in Myasthenia Gravis (搜索)
Cartesian Therapeutics employed the Olink Target 96 Inflammation panel to monitor cytokine responses in patients with generalized myasthenia gravis (搜索) (MG) participating in a phase 2b clinical trial of Descartes-08, an autologous, RNA-encoded anti-BCMA (搜索) CAR-T cell therapy.
Administering Descartes-08 in an outpatient setting led to durable clinical efficacy. Multiomic analysis revealed a precision retuning of self-reactivity, demonstrated by reduced activity of BCMA (搜索)+ plasma cells and plasmacytoid dendritic cells, alongside increased pro-immune function. Critically, Olink analysis confirmed that Descartes-08 administration was not associated with protein changes indicative of unwanted CAR-T cell therapy-induced inflammation.
After three months, positive effects on multiple markers associated with autoimmunity were observed, most notably reductions in IL-6, IL-24, CCL19, and ARTN. By month 12, additional proteins relevant to autoimmune inflammation and immune reset decreased, including TRAIL, EN-RAGE, TNFSF14, and TGF-β1. The specific changes in immune signatures without broad suppression support what researchers describe as a precision immune reset resulting in durable clinical improvement.
Custom Biomarker Panel Stratifies Kidney Outcomes in Type 2 Diabetes (搜索)
Chronic kidney disease (搜索) (CKD) impacts between 20% and 50% of patients with type 2 diabetes (搜索) (T2D) worldwide. Scientists from Eli Lilly and the Joslin Diabetes Center conducted a post hoc proteomic analysis of the AWARD-7 clinical trial for dulaglutide, a long-acting GLP-1 receptor agonist.
A custom 21-protein Olink Flex panel, termed the Joslin Kidney Panel (JKP), was designed from 64 circulating proteins previously linked to elevated risk of end-stage kidney disease (ESKD) in people with diabetes. The panel included key ESKD-associated markers such as ligands, inhibitors, immunoregulatory receptors, and TNF receptors.
The analysis revealed that 14 JKP markers increased over six months in patients on insulin glargine, while these same markers decreased in dulaglutide-treated individuals, with statistically significant between-group differences. The most notable differences were observed in eight TNF receptors and in mediators of apoptosis and inflammation.
Stratification by estimated glomerular filtration rate (eGFR) revealed that dulaglutide's effects on circulating JKP proteins were three times larger in patients with severe versus moderate kidney dysfunction. Variations in JKP protein responses were also observed when stratifying by HbA1c, BMI, or UARC.
These findings suggest that physicians can identify individuals who may benefit most from dulaglutide treatment regarding reduction in kidney outcome risk by examining the six-month decline in JKP protein concentrations according to baseline clinical variables.
The Broader Implications for Drug Development
"As multiomics technologies, like proteomics, evolve generating massive amounts of information, the real value lies in translating those signals into knowledge that can guide smarter decisions," said Jen-Chieh (Jay) Chuang, PhD, Director and Translational Biomarker Lead at Takeda Pharmaceuticals (搜索).
Dawn Waterworth, PhD, Executive Director of Immunology Translational Sciences at Johnson & Johnson Innovative Medicine, added: "We start by understanding the disease we want to treat as that defines everything else. Proteomics is just giving us a lot more in terms of identifying biomarkers that are really relevant to our processes."
These studies collectively illustrate how proteomics is moving beyond simple biomarker identification toward enabling actionable clinical decision-making, from target discovery and drug repurposing to patient stratification and therapeutic monitoring across diverse disease areas.