For many years, complement was viewed mainly as a circulating “attack system” that tags microbes and punches holes in their membranes. A recent review in the Journal of Clinical Investigation reframes this view, showing that complement is deeply embedded in the biology of the intestinal barrier, chronic inflammation, and colon cancer – and that precise complement modulation could unlock a new generation of therapies for gastrointestinal (GI) disease.
For drug developers, this evolving understanding creates both complexity and opportunity. The challenge is no longer simply “turn complement off,” but to tune specific pathways, locations, and time windows. This is exactly where specialized complement CRO support becomes strategically valuable.
Complement as a Gatekeeper of Intestinal Homeostasis
The intestine is protected by a multilayer barrier: mucus, a highly specialized epithelial sheet, and underlying immune cells. Disruption at any of these levels promotes increased permeability, microbial translocation, and a self-propagating cycle of inflammation.
Fig. 1 Complement in healthy colon, IBD, and colon cancer.1,2
Complement is woven into this system at multiple points:
- Local production – Intestinal epithelial cells, resident macrophages, dendritic cells, and other stromal cells synthesize complement components, not just the liver.
- Canonical functions – Opsonization, recruitment of phagocytes via C3a/C5a, and formation of the membrane attack complex (MAC) still matter in the gut, where they help clear pathogens and damaged cells.
- Non-canonical roles – Complement fragments signal through intracellular and tissue-restricted routes, influencing epithelial proliferation, tight junction integrity, metabolic pathways, and cross-talk with microbiota-sensing receptors.
Under homeostatic conditions, these layers of activity support barrier repair and controlled immune activation. When regulation fails, the same machinery can drive chronic inflammation and carcinogenesis.
From Inflammation to Cancer: When Complement Goes Off-Script
Complement can both protect against and promote intestinal disease, depending on context, timing, and cell type.
In inflammatory bowel disease (IBD), dysregulated complement is associated with:
- Increased epithelial permeability and loss of barrier integrity
- Elevated levels of anaphylatoxins such as C3a and C5a in inflamed tissue
- Skewed recruitment and activation of Th1, Th17, and myeloid populations in the lamina propria
In colon cancer, complement signaling becomes even more paradoxical:
- Some complement axes appear tumor-restraining early on, limiting initial transformation and supporting immunosurveillance.
- Others support an immunosuppressive microenvironment, fueling tumor growth, angiogenesis, and resistance to therapy.
- Experimental models suggest that interfering with the C5a–C5aR pathway can sensitize tumors to radiotherapy, while modulation of C3a/C3aR may influence the efficacy of immune checkpoint blockade.
These data point to complement not just as a biomarker of intestinal inflammation, but as a dynamic regulator of therapeutic response in the GI tract.
Therapeutic Opportunities Along the Complement Cascade
The clinical success of C5 blockade has already validated complement as a druggable space in systemic rare diseases. Eculizumab binds complement protein C5, preventing its cleavage and formation of the terminal complement complex C5b-9, thereby inhibiting complement-mediated hemolysis in conditions such as paroxysmal nocturnal hemoglobinuria.
The intestinal setting, however, calls for a broader and more refined toolkit:
- Upstream inhibition (C3, factor D, factor B) – Potential to reduce overall complement activation and opsonization in IBD or colitis-associated cancer, but with careful monitoring of infection risk.
- Terminal pathway blockers (C5, C5b-9) – Attractive when MAC-driven tissue damage dominates, and as combination partners with radiotherapy or chemotherapy.
- Receptor-targeted agents (C3aR, C5aR) – Fine-tuning local immune cell recruitment and polarization without completely shutting down complement effector function.
- Soluble regulators and engineered decoys – Mimicking or enhancing the activity of physiological regulators (e.g., CD46, CD55, CD59) to restore balance at the level of C3/C5 convertases.
Given the dual roles described in intestinal inflammation and cancer, success will depend on matching the right target, pathway, and modality to specific disease stages and patient subsets.
Bridging Biology and Drug Discovery with Creative Biolabs
Turning this complex biology into robust, de-risked drug candidates requires an integrated complement-focused platform – from target validation to functional screening and lead optimization. Creative Biolabs has built a dedicated Complement Therapeutics portfolio.
Key capabilities include:
Therapeutic antibody discovery and engineering
- Antibodies against core complement components (e.g., C3, C5)
- Antibodies targeting regulators and receptors (e.g., CD46, CD55, CD59, anaphylatoxin receptors) for pathway-specific modulation
Soluble complement regulators and component inhibitors
- Design, engineering, and functional optimization of recombinant regulators
- Protease inhibitors targeting complement-activating serine proteases
Receptor antagonists for anaphylatoxins
- C3aR and C5aR antagonist discovery campaigns to reshape inflammatory cell recruitment in intestinal tissues
Assay and analytics platforms purpose-built for complement biology
- The hemolysis assay platform offers multiple formats to profile classical, alternative, and lectin pathway activity and to quantify inhibition with high reproducibility
- Complement component assay panels covering key proteins such as C2, C4b, C5, C5a, C9, factor D, MBL, and factor I for pharmacodynamic monitoring and mechanism-of-action studies
Together, these services provide a one-stop solution for teams aiming to design next-generation complement therapeutics informed by cutting-edge intestinal biology.
Designing Smarter Complement Programs for Intestinal Disease
- Contextual target selection – Choosing whether to modulate C3, C5, or downstream receptors based on disease stage, microbiome status, and existing therapy (e.g., immunotherapy, radiation).
- Function-centric in vitro models – Using complement-sensitive epithelial, organoid, or co-culture systems to capture barrier integrity, cytokine patterns, and immune cell recruitment under controlled complement activation.
- Careful biomarker strategy – Combining systemic complement readouts (C3a, C5a, sC5b-9) with tissue markers and imaging of tumor microenvironment composition.
- Combination design from the outset – Planning how complement modulation will interface with checkpoint inhibitors, biologics targeting other inflammatory pathways, or standard chemo-/radiotherapy.
Creative Biolabs can support each of these steps with custom assay development, tailored antibody and inhibitor discovery, and iterative optimization guided by functional readouts rather than only static endpoints.
Conclusion: Turning Complement Complexity into Competitive Advantage
Complement is no longer a peripheral player, but a central and nuanced regulator of barrier integrity, immune orchestration, and therapy response in the GI tract.
For innovators in IBD and colorectal cancer drug development, this complexity should not be a barrier – it is a differentiator. By partnering with a specialized complement therapeutics provider, you can move beyond generic inhibitors and design pathway-, tissue-, and indication-specific strategies that better reflect real disease biology.
If you are planning or advancing a project in complement-mediated intestinal disease, the Complement Therapeutics team at Creative Biolabs is ready to collaborate. Get in touch to discuss how we can help you transform emerging insights in complement biology into first-in-class or best-in-class therapeutics.
References
- Krieg, Carsten, and Silvia Guglietta. “The complement system in intestinal inflammation and cancer.” The Journal of Clinical Investigation19 (2025). https://doi.org/10.1172/JCI188348
- Distributed under Open Access license CC BY 4.0, without modification.