Resources>Blog>Advancing Antibody Drug Research for Ulcerative Colitis: Innovations & Insights
Advancing Antibody Drug Research for Ulcerative Colitis: Innovations & Insights
Biointron2025-03-26Read time: 10 mins
Milestones in UC treatment. DOI: 10.1177/17562848221138160
Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by inflammation of the colonic mucosa. Standard therapeutic options include aminosalicylates, corticosteroids, and immunomodulators, all of which aim to control inflammation but often lack specificity and are associated with systemic adverse effects. Despite initial efficacy, many patients experience a loss of response or require escalation to more intensive therapies. In recent years, monoclonal antibodies (mAbs) have emerged as a targeted approach to modulating inflammatory pathways with improved specificity and favorable safety profiles, especially for patients unresponsive to conventional therapies.
Established Antibody Therapeutics for UC
Infliximab
Infliximab was the first biological agent approved for the treatment of UC. A chimeric IgG1 monoclonal antibody, infliximab binds to tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine in UC pathogenesis. Originally developed and validated in Crohn’s disease through the ACCENT 1 trial, infliximab’s application to UC was supported by pilot studies in steroid-refractory cases. Subsequent meta-analyses confirmed its efficacy in this population, showing significantly higher treatment response rates (OR: 2.96; 95% CI: 2.12–4.14) and reduced colectomy rates compared to ciclosporin.
Despite similar safety profiles and long-term colectomy-free survival rates between infliximab and ciclosporin, the ease of administration has led to a preference for infliximab in clinical practice. However, challenges such as anti-drug antibody (ADA) formation have emerged. ADA development has been associated with reduced clinical efficacy and higher incidence of infusion reactions, necessitating therapeutic drug monitoring and considerations for immunosuppressive co-therapy.
Adalimumab
Adalimumab, a fully human monoclonal antibody targeting TNF-α, was evaluated in the ULTRA 1 and 2 trials for induction and maintenance of remission in moderate-to-severe UC. Its subcutaneous administration route provides a patient-friendly alternative to intravenous infliximab, with comparable efficacy in TNF-driven inflammation. However, like infliximab, adalimumab is susceptible to primary non-response and secondary loss of response due to immunogenicity or pharmacokinetic factors.
Golimumab
Golimumab, another fully human anti-TNF-α monoclonal antibody, is administered subcutaneously. Preclinical data suggest it has higher binding affinity for TNF-α compared to infliximab and adalimumab, potentially enhancing its neutralization capacity. Clinical trials have demonstrated golimumab’s efficacy in inducing and maintaining remission in UC, though it faces similar resistance profiles in a subset of patients.
Despite the overall success of anti-TNF therapies, up to 30% of patients exhibit primary non-response, and many others lose responsiveness over time. These limitations have led to exploration of alternative immune pathways beyond TNF-α signaling.
The limitations of existing anti-TNF biologics have driven interest in next-generation antibody modalities that can enhance efficacy, reduce immunogenicity, and target alternative mechanisms.
Bispecific Antibodies
Bispecific antibodies capable of simultaneously targeting two distinct inflammatory mediators (e.g., TNF-α and IL-23) are being developed to address the multifactorial nature of UC inflammation. These agents may offer synergistic suppression of inflammatory signaling with a single therapeutic molecule.
Antibody Fragments and Nanobodies
Smaller antibody formats, including Fab fragments and nanobodies, are being investigated for their ability to penetrate inflamed tissues more effectively and reduce systemic exposure. Their compact size allows for improved mucosal distribution, which is particularly relevant for localized diseases like UC.
Fc Engineering
Modifying the Fc region of antibodies enables modulation of half-life, effector function, and interaction with Fc receptors. Engineering strategies are being employed to increase antibody stability, enhance mucosal retention, and minimize off-target immune activation.
Antibody–Drug Conjugates (ADCs)
While traditionally associated with oncology, ADCs are being explored for UC by conjugating anti-inflammatory payloads to gut-targeting antibodies. This approach allows for localized delivery of immunosuppressive agents to inflamed tissues, reducing systemic toxicity.
Novel Targets and Pathways in UC Pathogenesis
Recent discoveries in immunopathology have highlighted several key pathways beyond TNF-α that contribute to UC progression.
IL-12 and IL-23 Pathways
IL-12 and IL-23 share a common p40 subunit and drive differentiation of Th1 and Th17 cells, respectively. Ustekinumab, a monoclonal antibody targeting this p40 subunit, was initially approved for Crohn’s disease and later evaluated in UC through the UNIFI trial. In patients with moderate to severe UC, ustekinumab demonstrated statistically significant improvements in clinical remission, validating the role of the IL-12/23 axis in UC pathogenesis.
Vedolizumab
Vedolizumab is a humanized monoclonal antibody that selectively inhibits the α4β7 integrin, preventing T-cell homing to the gut by disrupting its interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1). This gut-selective mechanism reduces systemic immunosuppression while maintaining robust anti-inflammatory effects in intestinal tissues.
Th17 Pathway and IL-17
Emerging evidence suggests that a subset of UC patients may shift from a TNF-α-driven immune profile to one dominated by IL-17-producing Th17 cells. This has led to interest in therapeutic agents that target IL-17, IL-6, or their upstream regulators.
Itolizumab
Itolizumab is a novel immune-modifying monoclonal antibody targeting CD6. By inhibiting CD6-ALCAM interactions, itolizumab suppresses effector T cell proliferation while preserving regulatory T cells. In a Phase II clinical trial for moderate to severe UC, itolizumab demonstrated a 23.3% clinical remission rate at 12 weeks, compared to 20% for adalimumab and 10% for placebo. Clinical response rates were 63.3% for itolizumab versus 60% for adalimumab. Endoscopic remission occurred in 16.7% of patients in both treatment groups. The safety profile of itolizumab was comparable to that of adalimumab, supporting its potential as a competitive alternative.
Companion Diagnostics and Biomarker-Driven Strategies
With the expansion of antibody-based treatments, predictive biomarkers have become central to stratifying patients and guiding therapy.
Biomarker Use
Serum TNF-α levels, fecal calprotectin, and C-reactive protein (CRP) are commonly used to monitor treatment response. High baseline TNF-α has been associated with favorable outcomes in anti-TNF therapy, while persistent elevation may signal therapeutic failure.
Genomic and Transcriptomic Profiling
Genetic variants and transcriptional signatures associated with UC severity and therapeutic responsiveness are being incorporated into personalized treatment algorithms. For example, variants in the HLA-DQA1*05 allele have been linked to increased immunogenicity against infliximab.
Single-cell Technologies
Single-cell RNA sequencing has identified immune cell subsets and inflammatory signatures associated with drug response. These technologies support the rational design of targeted therapies and companion diagnostics.
Antibody Discovery Platforms for UC Applications
The development of UC-specific antibodies relies on advanced discovery platforms and validation models.
High-throughput Screening
Phage display and yeast surface display systems are employed to screen large antibody libraries for high-affinity binders against UC-associated antigens. Humanized and fully human antibody platforms minimize immunogenicity risks.
Epitope Mapping
Precise epitope identification facilitates the design of antibodies that avoid cross-reactivity with non-target tissues and optimize binding to inflamed mucosa.
Preclinical Validation
Patient-derived intestinal organoids and explanted mucosal tissues are used for ex vivo evaluation of antibody candidates. These models recapitulate patient-specific inflammatory profiles and provide functional validation before clinical trials.
Manufacturing and Delivery Challenges for UC Antibodies
Antibody therapeutics for UC face unique formulation and delivery considerations:
Production and Formulation: Manufacturing strategies prioritize high-yield expression systems, such as CHO cells, and stable formulations compatible with subcutaneous or intravenous administration. Formulations must balance viscosity, stability, and bioavailability.
Mucosal Delivery: Oral antibody formulations and encapsulation technologies are under development to achieve targeted delivery to the gut mucosa. Barriers include proteolytic degradation and poor absorption across the gastrointestinal epithelium.
Localized Delivery: Hydrogel-based systems and nanoparticle carriers are being evaluated for local delivery of antibodies to inflamed colonic tissue, aiming to maximize local efficacy while minimizing systemic exposure.
Regulatory and Market Landscape
The regulatory landscape for UC biologics continues to evolve, with increasing emphasis on immunogenicity assessment and biosimilar development.
Clinical Trial Activity
Multiple antibody candidates are in various stages of clinical evaluation, including bispecifics, anti-IL-23 agents, and CD6-targeting antibodies. Phase II and III trials are focused on head-to-head comparisons with established agents.
Biosimilars
As patents expire for first-generation biologics like infliximab and adalimumab, biosimilars are entering the market, increasing competition and driving down costs. Regulatory pathways require rigorous demonstration of similarity in pharmacokinetics, efficacy, and immunogenicity.
Outsourcing and CRO Role
Contract research organizations (CROs) and CDMOs are critical partners in antibody development, providing expertise in cell line development, process optimization, and regulatory compliance for both novel biologics and biosimilars. At Biointron, we are dedicated to accelerating antibody discovery, optimization, and production. Our team of experts can provide customized solutions that meet your specific research needs, including HTP Recombinant Antibody Production, Bispecific Antibody Production, Large Scale Antibody Production, and Afucosylated Antibody Expression. Contact us to learn more about our services and how we can help accelerate your research and drug development projects.
References:
Aslam, N., Lo, S. W., Sikafi, R., Barnes, T., Segal, J., Smith, P. J., & Limdi, J. K. (2022). A review of the therapeutic management of ulcerative colitis. Therapeutic Advances in Gastroenterology, 15, 17562848221138160. https://doi.org/10.1177/17562848221138160
