Predicting Response to Vedolizumab in Anti-TNF Refractory IBD

1. Context: The Translational Challenge

Patients with inflammatory bowel disease (IBD) who are refractory to anti-TNF therapies represent a significant unmet clinical need. Although vedolizumab is an established therapy, only a subset of patients derive clinical benefit, and response cannot currently be predicted with sufficient confidence prior to treatment.

From a translational science and drug development perspective, this uncertainty contributes to:

• Unnecessary patient exposure to ineffective biologics
• Increased clinical trial attrition
• Escalating development and healthcare costs

There is therefore a strong need for functional approaches that enable earlier, biologically grounded treatment decisions.

2. Approach: Functional Molecular Profiling in Native Patient Samples

This case study applied Physiological Inter-Molecular Modulation Spectroscopy (PIMS®) to assess therapeutic response ex vivo using patient-derived biological samples.

PIMS® is a label-free biophysical technology that detects functional molecular responses by measuring nanoscale changes in water molecule resonance following drug challenge. Because the biological sample remains in its native state, this approach captures real-time functional engagement of pharmacological signalling pathways, rather than indirect or static molecular markers.

To provide mechanistic understanding of response and resistance, Nematic Protein Organization Technique (NPOT®) was subsequently applied to identify the protein networks underlying the observed functional phenotypes.

3. Study Design

• Peripheral blood mononuclear cells (PBMCs) were obtained from anti-TNF refractory IBD patients
• Samples were analysed ex vivo using PIMS®
• Each sample was assessed at baseline and following incubation with vedolizumab
• Functional molecular responses were compared between clinically confirmed responders and non-responders

This design enabled direct assessment of drug-induced functional modulation within patient-specific biological matrices.

4. Key Evidence: Functional Stratification Using PIMS®

Clear differentiation between responders and non-responders

Figure 1. Representative PIMS® spectra generated from PBMC samples at baseline and following vedolizumab challenge.

PIMS® analysis revealed a clear and reproducible functional distinction between responders and non-responders:

• Non-responders showed no significant change in macromolecular interaction volume following exposure to vedolizumab
• Responders exhibited a pronounced increase in macromolecular interaction volume, indicating activation of relevant pharmacological signalling pathways

These functional differences were captured as distinct three-dimensional spectral fingerprints, demonstrating that therapeutic response could be predicted prior to clinical treatment.

5. Mechanistic Insight: Understanding Response and Resistance with NPOT®

Functional signalling networks explain clinical outcomes

Figure 2. NPOT®-derived protein interaction networks in responder and non-responder PBMC samples following vedolizumab challenge.

NPOT® analysis provided mechanistic interpretation of the functional differences detected by PIMS®:

• In both responders and non-responders, NPOT® identified the primary target of vedolizumab (α4β7 integrin)
• Only responders exhibited a distinct functional signalling network involving co-receptors and associated proteins linked to therapeutic efficacy
• Non-responders lacked this functional network, explaining the absence of clinical benefit

This analysis demonstrates that target presence alone is insufficient — functional network engagement is required for therapeutic response.

6. Predictive Biomarkers: Linking Function to Clinical Translation

Biomarkers associated with therapeutic response

NPOT® identified key proteins associated with response to vedolizumab, including:

• Platelet Factor 4 (PF4)
• Vitamin D-binding protein (GC)

These biomarkers provide a molecular basis for patient stratification and are supported by independent clinical evidence linking vitamin D status to vedolizumab response in IBD patients.

Together, these findings demonstrate how functional stratification can be translated into biomarker-driven clinical decision support.

7. Translational Value: Why This Matters

This case study illustrates how functional molecular profiling can support earlier, more confident decision-making in translational research and drug development.

8. Conclusion

By integrating PIMS®-based functional stratification with NPOT®-driven pathway analysis, this approach adds a decision-ready layer of evidence to translational science — without oversimplifying the underlying biology.