What are the therapeutic candidates targeting C5?

Introduction to Complement System and C5

Overview of the Complement System

The complement system is a critical component of the innate immune system consisting of more than 30 circulating and membrane-bound proteins that act in a cascade to defend against pathogens. Activation of this system occurs through the classical, lectin, and alternative pathways that all converge on central components such as C3 and finally lead to the formation of the membrane attack complex (MAC) capable of lysing target cells. In addition to direct lytic activity via MAC formation, complement activation produces bioactive fragments that serve as anaphylatoxins (e.g., C3a, C5a), which subsequently mediate inflammatory responses by recruiting and activating immune cells. In recent years, the understanding of this system’s multifaceted roles in immunosurveillance, inflammation, and tissue homeostasis has advanced considerably, with its contribution to many autoimmune, neoplastic, and inflammatory conditions being well recognized.

Role and Function of C5 in Immunology

C5 is one of the central proteins in the complement cascade and plays a pivotal role in linking the early activation events with the terminal effector functions of complement. Upon activation, C5 is cleaved by the C5 convertases generated by either the classical or alternative pathways. This cleavage yields two fragments: C5a, a potent anaphylatoxin, and C5b, which initiates the assembly of the MAC. C5a is known for its powerful pro-inflammatory effects—it acts via binding to its receptors (C5aR1 and C5aR2) to mediate chemotaxis, release of cytokines, and modulation of immune cell activities. Meanwhile, C5b associates with other complement proteins (C6–C9) to form MAC, a structure that directly lyses targeted cells. This dual functionality makes C5 a critical target in conditions where aberrant complement activation results in tissue damage, and its modulation is expected to abrogate both inflammatory and lytic mechanisms implicated in disease.

Therapeutic Candidates Targeting C5

Current Approved Therapies

A number of therapeutic agents targeting C5 have already achieved regulatory approval owing to their proven clinical efficacy in complement-mediated disorders.
• Eculizumab is the first approved anti-C5 monoclonal antibody that prevents the cleavage of C5 into C5a and C5b, thereby averting MAC formation and the subsequent inflammatory cascade. It is used primarily in paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and more recently in conditions such as myasthenia gravis and neuromyelitis optica spectrum disorder. Its mechanism of action is well characterized and is supported by extensive clinical data demonstrating a reduction in hemolysis and improvement in patient outcomes.
• Ravulizumab is a second-generation anti-C5 monoclonal antibody with a modified Fc region engineered to extend its half-life. This allows for an increased dosing interval—typically every eight weeks—reducing the treatment burden on patients while maintaining comparable efficacy to eculizumab. Its approval for similar indications such as PNH and aHUS has provided an alternative for patients who require a less frequent dosing regimen.

Emerging Therapeutic Candidates

In addition to the approved therapies, various novel agents targeting C5 are under clinical investigation or in preclinical development with the aim of improving therapeutic efficacy, administration convenience, and safety profiles.
• Zilucoplan is a synthetic macrocyclic peptide that targets C5 by binding with sub-nanomolar affinity. By preventing the cleavage of C5, zilucoplan disrupts the generation of both C5a and C5b and has shown efficacy in phase II studies particularly in myasthenia gravis. Its small peptide structure also offers the potential for subcutaneous administration, thereby providing a more convenient mode of delivery compared to intravenous antibodies.
• Crovalimab is another promising anti-C5 candidate currently being evaluated in clinical trials. It is a monoclonal antibody designed to inhibit the terminal complement pathway and provides the potential advantage of an alternative binding epitope and pharmacokinetic profile distinct from that of eculizumab and ravulizumab. Early phase trials are investigating its safety and efficacy in patients with complement-mediated diseases, with an emphasis on its ability to maintain complete inhibition of complement-mediated lysis.
• Cemdisiran is an innovative RNA interference (RNAi) therapeutic that targets the mRNA encoding C5, leading to reduced hepatic synthesis of the protein. By decreasing circulating levels of C5, cemdisiran indirectly prevents its cleavage and the subsequent downstream effects. The use of RNAi technology represents a distinct mechanism compared to monoclonal antibodies and may offer the advantage of subcutaneous administration along with potential long-term suppression after a limited dosing schedule.
• Emerging agents such as avacincaptad pegol—though its primary label may pertain to complement inhibition more broadly—also demonstrate activity at the level of C5. This candidate is designed to achieve robust control of complement activity and mitigate both intravascular hemolysis and inflammatory responses.
• Additional novel approaches include the exploration of orally bioavailable small molecule inhibitors. For example, recent reports indicate progress in the development of oral C5 inhibitors by companies like BioCryst Pharmaceuticals. These agents aim to replicate the efficacy of injected monoclonal antibodies while overcoming the challenges inherent in parenteral administration.
• Furthermore, inhibitors derived from natural sources such as components found in tick saliva (e.g., the CirpT family) have been structurally characterized and show unique binding modes to C5. These inhibitors block complement activation via interaction with the C5_MG4 domain, offering an exciting new avenue in the design of small-molecule or peptide-based therapeutics.

Mechanisms of Action

Inhibition of C5 and Downstream Effects

The central strategy behind targeting C5 involves abrogating its cleavage into the active fragments C5a and C5b. By preventing this key step, therapeutic agents disrupt both the generation of a potent anaphylatoxin and the initiation of MAC formation. In approved therapies such as eculizumab and ravulizumab, the monoclonal antibodies bind specifically to C5 with high affinity, thereby blocking its cleavage by convertases. This results in the suppression of intravascular hemolysis, reduced inflammatory cell activation, and diminished cytokine release. In the case of RNAi approaches like cemdisiran, the mechanism is distinct; by silencing C5 mRNA within hepatocytes, the overall protein level of circulating C5 is reduced, leading to lowered substrate availability for convertases and ultimately preventing the cascade from progressing.

Comparison of Mechanisms Among Candidates

While the end goal—the inhibition of C5 cleavage—is shared among different therapeutic candidates, the mechanisms and modalities vary considerably. Monoclonal antibodies (eculizumab, ravulizumab, crovalimab) achieve inhibition via direct binding to C5, but they differ in pharmacokinetic properties, binding epitopes, and dosing regimens. For instance, ravulizumab’s engineered Fc modification permits enhanced dissociation in acidic endosomal environments, allowing it to be recycled back into circulation and thus extending its half-life compared to its predecessor. In contrast, the synthetic peptide zilucoplan, due to its small size and mechanical properties, is amenable to subcutaneous administration and may achieve rapid tissue penetration. RNAi-based agents like cemdisiran work by reducing the synthesis of the target protein at the transcriptional level, which represents an entirely different approach compared to the blockade of the protein’s activity post-synthesis. Natural product-derived inhibitors, such as those from the CirpT family, also introduce alternative binding architectures and may offer distinct advantages in binding kinetics and specificity. These differences have a profound impact on factors such as route of administration, dosing frequency, side effect profile, and overall clinical utility.

Clinical Applications and Research

Current Clinical Trials and Studies

Clinical investigations into these therapeutic candidates are extensive and aim to establish both efficacy and safety across a range of complement-mediated disorders. Eculizumab and ravulizumab have already demonstrated their clinical utility in disorders like paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, achieving marked reductions in hemolytic activity as measured by lactate dehydrogenase levels and improved patient quality of life.
Emerging therapies under clinical development are being evaluated in various phases of trials. Zilucoplan has undergone phase II studies in myasthenia gravis, where its ability to control disease activity was demonstrated through validated endpoints such as improvements in clinical muscle strength and reduction in biomarkers associated with complement activation. Crovalimab is currently being tested in early phase clinical trials, with studies focusing on safety, pharmacokinetics, and its capacity for comprehensive complement inhibition. RNAi therapeutics such as cemdisiran are being evaluated for their ability to modulate C5 levels in patients with complement-mediated hemolytic disorders. In preclinical models as well as in early human trials, cemdisiran demonstrates durable suppression of circulating C5 and corresponding decreases in hemolytic activity.
The use of humanized animal models, such as humanized C5 mice, has further allowed investigators to compare the pharmacodynamics and clearance rates of these anti-C5 antibodies. For instance, switching regimens in these models have shown sustained suppression of hemolytic activity when transitioning from established compounds like eculizumab to novel candidates such as pozelimab. Such studies provide an essential translational bridge from preclinical findings to clinical utility and offer insights into dose optimization and administration schedules.

Potential Indications and Efficacy

The therapeutic candidates targeting C5 have been primarily developed to address diseases driven by excessive complement activation. The strongest clinical indications include paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and recently, myasthenia gravis. However, their utility is also being explored in a broader range of conditions where complement-mediated inflammation plays a pivotal role. These include neuromyelitis optica, age-related macular degeneration, and even certain types of autoimmune and renal diseases. The rationale behind these indications is based on the understanding that uncontrolled C5 activation contributes to both intravascular hemolysis and extravascular inflammatory damage.
Efficacy assessments in clinical trials often focus on key biomarkers such as lactate dehydrogenase (LDH) levels, frequency of transfusions, and clinical scores related to muscle strength or neurological impairments. For example, in clinical trials of eculizumab and ravulizumab, reductions in LDH levels have been directly correlated with a decrease in hemolysis and improved patient outcomes. Emerging candidates like zilucoplan have similarly been evaluated using both biochemical markers and patient-reported outcomes, indicating significant clinical improvements over placebo in early studies.
Furthermore, exploratory studies using RNAi approaches have established that reducing C5 levels at the synthesis level may not only suppress hemolytic activity but might also reduce the frequency of breakthrough hemolysis episodes, a phenomenon sometimes observed with antibody-based therapies. These therapeutic candidates are being evaluated across different patient populations and disease stages, ensuring that they address both acute and chronic manifestations of complement-mediated injury.

Challenges and Future Directions

Current Challenges in Targeting C5

Despite the promise shown by both approved and emergent therapeutic candidates, several challenges remain in the targeting of C5. One of the primary issues is the method of administration. Current monoclonal antibodies like eculizumab and ravulizumab require intravenous infusions, which can be inconvenient and costly over a patient’s lifetime. Additionally, while these high molecular weight agents are effective, they can also provoke immunogenic responses in certain patients and may lead to breakthrough hemolysis due to incomplete complement blockade, particularly if dosing intervals are not optimal.
Another challenge is the residual activity of upstream complement components. Although blocking C5 prevents the generation of C5a and MAC, it does not inhibit earlier steps in the cascade; persistent proximal complement activation can result in C3 opsonization and extravascular hemolysis, which is seen in some patients receiving anti-C5 therapy. With regard to RNAi therapeutics like cemdisiran, while the approach is promising due to the potential for long-lasting effects from limited dosing, issues such as delivery, off-target effects, and the durability of mRNA silencing in vivo remain significant hurdles.
Moreover, the cost of therapy is a major consideration. Agents such as eculizumab are among the most expensive drugs on the market, and while innovations like ravulizumab reduce the dosing frequency, their high production costs continue to limit broader access. Finally, although novel candidates such as orally bioavailable small molecules or peptides derived from natural sources show promise, challenges remain in ensuring adequate bioavailability, avoiding rapid metabolism and clearance, and achieving a favorable therapeutic index.

Future Research Directions and Innovations

Looking ahead, research in therapeutics targeting C5 is pivoting towards innovations that overcome the limitations of current therapies. One promising avenue is the development of orally bioavailable agents. Such developments could revolutionize administration by allowing patients to switch from intravenous or subcutaneous injections to oral dosing, thereby greatly enhancing convenience and adherence.
Advances in genetic and RNA-based therapies offer another exciting frontier. For example, further optimization and clinical validation of RNAi therapeutics like cemdisiran could result in treatment regimens that require fewer administrations and offer sustained complement suppression. In parallel, developments in nanotechnology and targeted drug delivery systems hold promise for achieving precise tissue-targeted therapy, reducing systemic exposure, and potentially limiting off-target effects.
Other future directions include the modulation of complement activity through combination therapies. By pairing anti-C5 agents with inhibitors that target other elements of the cascade or with immunomodulatory drugs, clinicians may be able to more comprehensively control both intravascular and extravascular complement-mediated processes. In addition, there is growing interest in exploring allosteric inhibitors and novel binding modalities (e.g., inhibitors derived from tick saliva like the CirpT family) that may offer more selective inhibition of specific complement pathways. These novel agents might provide a means to tailor inhibition specifically for the alternative or classical pathway while preserving some degree of host defense.
Finally, more detailed biomarker studies and patient stratification methodologies are needed. The identification of predictive markers that correlate with response to complement blockade will be essential in guiding personalized treatment. By using molecular diagnostics and monitoring levels of C5, C5a, and other downstream biomarkers, clinicians could better tailor therapies to individual patient needs and adjust dosing regimens in real time.

Conclusion

In conclusion, therapeutic candidates targeting C5 span a broad spectrum that includes established, approved agents as well as a diverse pipeline of emerging candidates. Current licensed therapies such as eculizumab and ravulizumab have paved the way by demonstrating that effective inhibition of C5 cleavage yields significant clinical benefits in diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and other complement-mediated conditions. These drugs function by directly binding C5 to block its cleavage, thereby simultaneously suppressing the generation of the potent anaphylatoxin C5a and the assembly of the terminal complement complex.

From the emerging pipeline, synthetic peptides like zilucoplan offer the benefit of subcutaneous administration along with rapid tissue penetration, while novel monoclonal antibodies such as crovalimab are progressing through early clinical investigations and show promise with potentially differentiated binding kinetics and safety profiles. Meanwhile, RNAi-based therapeutics like cemdisiran are exploring a fundamentally different mechanism by downregulating the synthesis of C5, thereby achieving sustained inhibition over extended dosing intervals. Natural product-derived inhibitors, including those from tick saliva (the CirpT family), add further diversity by introducing unique structural and mechanistic paradigms to inhibit complement activation.

Mechanistically, these agents can be broadly grouped based on whether they physically block the C5 molecule’s cleavage or reduce its production at the mRNA level. Each modality presents advantages and challenges in terms of pharmacodynamics, pharmacokinetics, and clinical practicality. While monoclonal antibodies exhibit robust and complete inhibition, issues such as the need for repeated intravenous dosing and high cost remain. Conversely, emerging agents aim to balance efficacy with patient convenience by offering subcutaneous or oral administration options, longer dosing intervals, and improved biodistribution.

Clinically, existing studies underscore that the inhibition of C5 results in significant reductions in hemolysis and inflammation; however, residual complement activity and breakthrough hemolysis observed in some patients underscore the need for further refinement. Ongoing clinical trials continue to evaluate these candidates across a range of complement-mediated syndromes, with promising indications for diseases beyond PNH and aHUS. Future research directions prioritize the development of novel delivery systems, combination therapies that target multiple points along the complement cascade, and the identification of robust biomarkers to guide personalized treatment approaches.

Overall, targeting C5 remains a dynamic and evolving field within complement therapeutics. With multiple candidates in various stages of development, the future holds the promise of expanding treatment options for patients with complement-mediated disorders. Continued innovations in drug design, formulation, and patient stratification are expected to overcome current challenges and pave the way for next-generation therapies that deliver enhanced efficacy, safety, and patient convenience. The integration of advanced platforms ranging from monoclonal antibodies and peptides to RNAi therapeutics and novel small molecules ensures a multifaceted approach to modulating the complement system, thereby ushering in an era of personalized and targeted complement inhibition.