What are the therapeutic candidates targeting IL-17A?

Introduction to IL-17A
IL-17A is a pro‐inflammatory cytokine that plays a central and multifaceted role within the immune system. It is primarily secreted by T helper 17 (Th17) cells as well as by other innate-like lymphocytes such as γδ T cells and innate lymphoid cells. Over the past two decades, extensive research—supported by both basic and translational studies—has elucidated the importance of IL-17A as a downstream mediator that links innate immunity with adaptive immune responses. Its production is tightly regulated by cytokines such as IL-23, and its signaling is mediated via a heterodimeric receptor complex that primarily involves IL-17RA and IL-17RC. The delicate balance in the activity of IL-17A is crucial for host defense mechanisms against extracellular bacteria and fungi, yet when dysregulated, IL-17A becomes a potent driver of chronic inflammation. This dual role underlies its appeal as a therapeutic target for a wide array of inflammatory and autoimmune diseases.

Role of IL-17A in the Immune System
IL-17A is recognized as one of the signature cytokines produced by Th17 cells. It contributes to the recruitment of neutrophils and other myeloid cells by inducing the expression of chemokines (for example, CXCL1 and CCL20) and inflammatory mediators in various cell types, including epithelial cells, fibroblasts, and endothelial cells. The signaling cascade initiated by IL-17A involves the activation of canonical pathways such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). These pathways culminate in the transcription of a broad spectrum of pro-inflammatory genes. Importantly, IL-17A not only acts as a transcriptional activator but also plays a critical role in stabilizing mRNA transcripts of inflammatory cytokines, thereby amplifying the inflammatory response. In healthy conditions, IL-17A is essential for maintaining mucosal barrier integrity and defense against pathogens, but an aberrant or chronic upregulation of IL-17A can drive pathological inflammation.

Diseases Associated with IL-17A
Numerous inflammatory diseases have been linked to elevated IL-17A levels. Its overproduction has been implicated in immune-mediated disorders such as psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel diseases, among others. In psoriasis, for example, IL-17A is a critical effector molecule that promotes keratinocyte hyperproliferation and neutrophil infiltration, ultimately driving the characteristic skin lesions. Similarly, in rheumatoid arthritis, IL-17A contributes to joint inflammation and bone erosion by inducing the release of matrix metalloproteinases and other osteoclast-activating factors. In addition, evidence from various studies suggests that targeting IL-17A could have therapeutic benefits in certain types of uveitis and even in some malignancies by modulating the immune suppressive microenvironment. Thus, IL-17A represents an attractive and validated target for therapeutic intervention across different disease contexts.

Therapeutic Candidates Targeting IL-17A
Therapeutic approaches aimed at targeting IL-17A have evolved considerably over recent years. Both biologic drugs in the form of monoclonal antibodies and emerging small molecule inhibitors, peptide antagonists, and novel antibody formats have been developed. These therapeutic candidates are designed to neutralize IL-17A activity through direct binding to the cytokine, blockade of its receptor, or interference with downstream signaling. The candidates can be broadly classified into those that are already approved for clinical use and those that are in various stages of development.

Current Approved Therapies
The most well‐established therapeutic candidates targeting IL-17A are humanized monoclonal antibodies. Their development has been driven by robust clinical evidence demonstrating remarkable efficacy, particularly in dermatological indications:

• Secukinumab – Marketed as Cosentyx, secukinumab is a fully human IL-17A inhibitor that has dramatically improved outcomes in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. It works by binding directly to IL-17A, thereby preventing its interaction with the IL-17 receptor complex and subsequent inflammatory signaling.

• Ixekizumab – Marketed as Taltz, ixekizumab is another monoclonal antibody that selectively neutralizes IL-17A. Clinical trials have demonstrated that ixekizumab provides rapid and sustained skin clearance in psoriasis, along with favorable outcomes in other IL-17A–driven conditions.

• Brodalumab – Although brodalumab does not bind IL-17A directly, it targets the IL-17 receptor A (IL-17RA), thereby inhibiting signaling initiated by IL-17A as well as IL-17F. While approved in some regions for the treatment of psoriasis, its unique mechanism makes it an important part of the IL-17 therapeutic landscape.

Each of these approved therapies has established a strong record of efficacy and safety in large-scale clinical trials, and their continued real-world use further validates the therapeutic targeting of IL-17A in inflammatory diseases.

Emerging Therapies in Development
Beyond the approved biologics, a number of emerging candidates targeting IL-17A are in various stages of research and clinical trials. These novel approaches aim to address some of the limitations associated with monoclonal antibodies, such as high cost, the need for parenteral administration, immunogenicity, and long serum half-lives, which can limit dosing flexibility. Several promising avenues include:

• Small Molecule Inhibitors – Ongoing research has identified small molecule antagonists that can disrupt the interaction between IL-17A and its receptor. Recent studies have uncovered macrocyclic compounds and non-macrocyclic small molecules that bind to novel sites on the IL-17A dimer, particularly at a previously undescribed C-terminal site. One such study demonstrated the design and optimization of macrocyclic IL-17A inhibitors with binding affinities in the nanomolar range and functional inhibition of IL-17A-induced cellular signaling. Small molecule inhibitors offer the potential for oral bioavailability and faster pharmacokinetic modulation compared to injectable antibodies.

• Peptide-Based Inhibitors – Specific peptide inhibitors that target IL-17A by mimicking its active binding region have been developed. Such peptides can competitively inhibit the binding of IL-17A to its receptor. In silico mutagenesis and docking studies have refined the sequences of these peptides to improve their binding affinity and stability. Patents describe novel peptide inhibitors and ligand modulators that provide a new frontier in targeting IL-17A with potentially lower immunogenicity and cost of production.

• Nanobodies and Antibody Fragments – Next-generation therapeutic candidates include nanobodies, derived from camelid antibodies, which are much smaller than conventional monoclonal antibodies and can be engineered for enhanced tissue penetration and rapid clearance. For instance, compounds under development by companies such as MoonLake Immunotherapeutics are exploring nanobody-based inhibitors targeting both IL-17A and IL-17F, with the promise of improved efficacy and safety profiles.

• Novel Antibody Formats – Innovative biologic modalities, such as bispecific antibodies that target IL-17A in combination with IL-17F (as seen with bimekizumab) or antibodies that target a critical active sequence of IL-17A (such as Ab-IPL-IL17), have shown promising preclinical and early clinical data. Ab-IPL-IL17, for example, specifically binds to the active peptide sequence of IL-17A, neutralizing its activity with potentially improved safety and tolerability compared to reference antibodies.

• IL-17A Modulators from Patents – A series of recently published patents describe novel ligands and pharmaceutical compositions that modulate IL-17A activity. These compounds include diverse formats ranging from small molecule mimetics to engineered protein scaffolds that may be harnessed in the treatment or prevention of inflammatory diseases and cancer.

Collectively, these emerging candidates are driving a new era of IL-17A targeting therapies that are designed to be more convenient (potential for oral administration), economically feasible, and adaptable to personalized treatment regimens.

Mechanisms of Action
Understanding the mechanisms by which therapeutic candidates targeting IL-17A work is key to appreciating their clinical impact as well as guiding the development of next-generation agents.

How IL-17A Inhibitors Work
The fundamental mechanism of IL-17A inhibitors involves the blockade of IL-17A from binding to its receptor complex, thereby interrupting the signaling cascade that would otherwise lead to activation of NK-κB, MAPKs, and subsequent production of a wide array of pro-inflammatory mediators. Monoclonal antibodies such as secukinumab and ixekizumab directly bind to IL-17A, effectively neutralizing the cytokine before it can interact with IL-17 receptors on target cells. In contrast, receptor blockers like brodalumab inhibit the signaling by binding to IL-17RA, thus preventing IL-17A (and IL-17F) from engaging with the receptor and initiating downstream inflammatory events.

Small molecule inhibitors and peptide-based therapeutics, though mechanistically distinct from antibodies, operate on similar principles. Structural studies have elucidated binding sites on the IL-17A dimer that are critical for its interaction with receptors. By occupying these sites, small molecules can allosterically distort the functional conformation of IL-17A, thereby preventing receptor engagement. This mechanism not only enables suppression of the inflammatory response at the molecular level but also potentially offers the benefits of reversible binding and oral administration. Nanobodies and engineered antibody fragments also function by binding to IL-17A or its receptor epitopes, and their reduced size can afford improved tissue penetration, particularly in sites where dense cellular architectures limit the diffusion of larger molecules.

Comparison of Different Therapeutic Approaches
An important aspect of IL-17A therapy is the variety of approaches that have been adopted, each with its own advantages and limitations:

• Monoclonal antibodies (e.g., secukinumab, ixekizumab) offer high specificity and strong binding affinity, leading to robust neutralization of IL-17A. However, their large molecular size necessitates parenteral administration and is associated with a long serum half-life, which can complicate dosing adjustments and increases production costs.

• Receptor blockers such as brodalumab, by targeting IL-17RA, exhibit a broader inhibitory profile (blocking several cytokines such as IL-17A and IL-17F). This broader targeting may have both advantages and drawbacks: while it can provide a more comprehensive suppression of inflammatory signals, it may also block the beneficial homeostatic functions mediated via IL-17 receptors on non-immune cells.

• Small molecule inhibitors, including macrocyclic compounds designed to bind new sites on IL-17A, promise the possibility of oral dosing, reduced production costs, and more rapid pharmacokinetic modulation. Their development, however, is more challenging because disrupting protein–protein interactions with small molecules requires precise binding to flat and large interfaces.

• Peptide-based inhibitors and nanobodies offer an intermediate approach. Peptides can be synthetically produced, potentially reducing immunogenicity and cost, while nanobodies provide the advantage of enhanced tissue penetration due to their small size. Nevertheless, these formats may require further modifications to improve stability and extend their half-life in vivo.

Each of these therapeutic modalities has been designed to mitigate the overactive IL-17A signaling responsible for pathological inflammation while preserving the cytokine’s critical functions in host defense. The choice of approach may ultimately depend on the disease context, patient-specific factors, and the desired pharmacokinetic and pharmacodynamic profile.

Clinical Trials and Efficacy
Multiple clinical trials have provided substantial evidence to support the effectiveness of IL-17A inhibitors in a range of diseases, particularly in dermatology. Clinical investigations have not only focused on efficacy endpoints but also on long-term safety and patient tolerability.

Overview of Key Clinical Trials
The approved monoclonal antibodies have undergone rigorous testing in randomized controlled trials. Secukinumab was evaluated in several large-scale phase III clinical trials that demonstrated significant reductions in the Psoriasis Area and Severity Index (PASI) score and improvements in quality-of-life measures. These trials established secukinumab’s efficacy in plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, leading to its wide regulatory approval and subsequent clinical use.

Similarly, ixekizumab has been tested across multiple phase II and III trials. Key studies demonstrated rapid skin clearance and sustained remission over extended treatment durations. The performance of ixekizumab was further confirmed through head-to-head comparisons with other cytokine-targeting agents, establishing its status as a highly effective IL-17A inhibitor.

In addition to these antibody-based therapies, emerging candidates such as bimekizumab—a bispecific antibody that targets both IL-17A and IL-17F—have advanced into late-stage trials. Bimekizumab has shown promise by offering rapid onset of improvement with sustained efficacy in psoriasis and psoriatic arthritis, as evidenced by PASI75 and PASI90 response rates. Early clinical trials with novel formats such as Ab-IPL-IL17 have provided preliminary evidence of comparable or enhanced efficacy to reference products, with studies highlighting its potential to reduce unwanted immune responses and adverse hematological side effects.

On the safety front, the overall tolerability of IL-17A inhibitors has been well documented, although certain risks—such as an increased susceptibility to infections—have been noted. The long-term clinical trials emphasize that while adverse events are mostly mild, careful patient monitoring remains essential. Furthermore, small molecule inhibitors and peptide therapeutics are still primarily in the investigational stage, and early-phase clinical trials or preclinical studies have begun to outline their efficacy profiles and safety margins.

Efficacy and Safety Data
Data from clinical trials indicate that IL-17A inhibitors provide rapid and substantial clinical improvement, particularly in psoriasis where treatment can result in PASI75 responses in more than 80% of patients. Secukinumab and ixekizumab, for example, have both shown dramatic improvements in skin clearance within 12 weeks of treatment, with a favorable safety profile that has been confirmed over several years of follow-up. Brodalumab, by virtue of receptor blockade, also demonstrates significant efficacy; however, its broader mechanism of action demands a nuanced evaluation of safety outcomes.

Emerging therapies such as small molecule inhibitors are still being evaluated, but preclinical data suggest that these agents are capable of effectively disrupting IL-17A signaling with an acceptable toxicity profile. Early-phase trials with compounds developed through structure-guided drug design have revealed IC50 values in the low-micromolar to nanomolar range, and safety assessments indicate that adverse effects can be limited through proper dosing calibration. Nanobody-based inhibitors, due to their smaller size, have demonstrated enhanced tissue penetration with early safety data suggesting a lower risk of systemic immunosuppression.

Overall, while biologics remain the gold standard in terms of clinical efficacy against IL-17A–mediated inflammation, emerging therapies are actively addressing some of the limitations of antibody-based drugs (such as parenteral administration and cost) by providing alternative mechanisms of inhibition through small molecules and peptides. The clinical trial data thus far underscore the transformative impact of IL-17A targeting on disease outcomes, while also highlighting the need for ongoing research to further refine these therapies.

Future Directions and Challenges
The field of IL-17A targeted therapies is rapidly evolving, and several challenges remain in optimizing these treatments for broader clinical utility. Future research and development efforts are focusing not only on improving efficacy and safety but also on expanding therapeutic options that overcome current limitations.

Research and Development Challenges
One major challenge in the development of IL-17A inhibitors is the complexity of protein–protein interactions. In the case of small molecule inhibitors, achieving high affinity and specificity while interfering with a large, flat protein interface (such as the IL-17A dimer) is technically challenging. Structural studies have helped identify novel binding sites (e.g., the recently discovered C-terminal site) and inform rational drug design; however, translating these findings into clinically effective oral therapies remains an ongoing endeavor.

Another difficulty is balancing the immunosuppressive effects with the risk of infections. Since IL-17A is critical for host defense against certain pathogens, its prolonged blockade may predispose patients to opportunistic infections. This safety concern necessitates careful patient selection and monitoring during both clinical trials and long-term treatment. Moreover, while monoclonal antibodies have proven effective, they are expensive to manufacture and administer, and their long half-lives may limit dosing flexibility in cases where rapid modulation of immune function is needed. The development of alternative modalities (such as nanobodies, peptides, and small molecules) is aimed at addressing such limitations, but these candidates must still demonstrate comparable efficacy and safety in rigorous clinical trials.

Immunogenicity is another consideration across different therapeutic classes. While humanized monoclonal antibodies minimize the risk of anti-drug antibody formation, peptide-based and small molecule inhibitors can sometimes trigger immune responses that may diminish their efficacy over time. Therefore, extensive preclinical and clinical testing is required to assess long-term immunogenicity and ensure sustained therapeutic benefits.

Regulatory challenges also persist, particularly as innovative therapeutics such as nanobodies and next-generation small molecules represent relatively new classes of drugs. Regulatory agencies require comprehensive data on pharmacokinetics, biodistribution, and long-term safety profiles, which can extend the time and cost required to bring these agents to market. Additionally, because some of these emerging therapies offer new modes of administration (such as oral dosing), establishing bioequivalence and ensuring acceptance by clinicians and patients remains an important hurdle.

Future Prospects in IL-17A Targeting Therapies
Looking ahead, the therapeutic landscape for IL-17A inhibition is expected to become even more diverse. As our understanding of the IL-17 signaling network deepens, future prospects include:

• Refinement of Small Molecule Inhibitors – Continued optimization through structure-guided drug design is likely to yield orally bioavailable small molecules that specifically target IL-17A with high potency. These agents have the potential to revolutionize treatment by offering more convenient administration routes, lower manufacturing costs, and improved patient compliance.

• Development of Combination Therapies – Given the complex immunopathology of IL-17A–related diseases, future strategies may involve combining IL-17A inhibitors with agents that target other inflammatory mediators (e.g., TNF-α or IL-23). Such combination therapies could provide synergistic effects and address cases where monotherapy falls short of fully reversing inflammation. Early studies have shown that simultaneous neutralization of IL-17A along with other cytokines may improve disease control, and ongoing research is expected to further clarify these relationships.

• Personalized Medicine Approaches – As biomarkers that predict response to IL-17A inhibitors become more refined, personalized treatment regimens tailored to individual patient profiles may emerge. This approach could enhance efficacy and reduce adverse effects by ensuring that only patients who are likely to benefit from IL-17A blockade receive these therapies.

• Innovative Drug Formats – The emergence of nanobodies, engineered antibody fragments, and peptide-based therapies represents a significant advance in the field. These formats can potentially overcome some of the limitations of conventional monoclonal antibodies, including tissue penetration, immunogenicity, and cost. With further clinical validation, these novel agents could become part of the standard therapeutic arsenal against IL-17A–mediated diseases.

• Improvement in Delivery Methods – Future advancements in drug delivery technology may also facilitate targeted therapy with IL-17A inhibitors. For instance, localized delivery to affected tissues (such as the skin in psoriasis) could limit systemic exposure and reduce side effects while maintaining high local drug concentrations. Novel formulations and delivery devices are therefore key areas of research moving forward.

• Addressing Safety and Tolerability Issues – Ongoing efforts to elucidate the long-term impact of IL-17A blockade will be central to expanding the use of these therapies. Innovative clinical trial designs, post-marketing surveillance, and real-world studies will continue to assess risks such as infection, immunosuppression, and other off-target effects. Adjustments in dosing strategies and patient monitoring protocols will contribute to safer use of IL-17A inhibitors across diverse patient populations.

Conclusion
In summary, the therapeutic candidates targeting IL-17A can be broadly divided into current approved biologics and emerging therapies under active development. Approved therapies such as secukinumab, ixekizumab, and receptor-blocking agents like brodalumab have already transformed the management of diseases such as psoriasis, psoriatic arthritis, and ankylosing spondylitis by directly neutralizing IL-17A or its receptor and thereby inhibiting its downstream inflammatory signaling. Emerging therapeutic approaches are expanding the landscape considerably. These include small molecule inhibitors that offer the potential for oral dosing and rapid pharmacokinetic modulation, peptide-based inhibitors that can competitively block the IL-17A receptor interaction, nanobody-based agents that promise enhanced tissue penetration and lower immunogenicity, and innovative antibody formats such as Ab-IPL-IL17 which may offer improved safety and efficacy profiles.

Mechanistically, these diverse therapeutic strategies converge on a common objective: the inhibition of IL-17A signaling by preventing the binding of IL-17A to its receptor complex, thus blocking activation of key pro-inflammatory pathways such as NF-κB and MAPK. Each therapeutic approach—from monoclonal antibodies to small molecules—has its own advantages and limitations. Monoclonal antibodies demonstrate excellent efficacy but are limited by administration route and cost, whereas small molecules and peptides promise greater convenience and cost-effectiveness while still requiring careful design to achieve sufficient binding affinity and specificity.

Robust clinical trials have provided extensive evidence of the efficacy and safety of IL-17A inhibition in inflammatory diseases. Key trials demonstrate that patients treated with agents such as secukinumab and ixekizumab experience rapid improvements in clinical symptoms and quality-of-life measures, with high PASI response rates and durable disease remission. Emerging therapies are gradually entering clinical evaluation phases, and early data from novel agents such as bimekizumab and Ab-IPL-IL17 show promise in terms of both efficacy and safety. Nonetheless, ongoing research is crucial to fully address potential challenges including immunogenicity, long-term adverse effects, optimization of dosing regimens, and the development of personalized treatment approaches.

Future directions in IL-17A targeting therapies are likely to involve further refinement of small molecule inhibitors, exploration of combination therapy strategies to enhance efficacy, and the advancement of innovative drug formats that overcome the current limitations of biologic therapies. Research focused on identifying biomarkers predictive of response will enable more tailored treatment strategies and ultimately improve patient outcomes. Advances in drug delivery and formulation are also anticipated to enhance safety and minimize systemic side effects. Despite the challenges, the therapeutic promise of IL-17A inhibitors remains immense, making them a focal point for future research and clinical development in the quest to treat inflammatory and autoimmune diseases more effectively.

In conclusion, the therapeutic candidates targeting IL-17A encompass a rich and evolving spectrum of modalities—from approved monoclonal antibodies to an array of emerging small molecules, peptides, nanobodies, and innovative antibody formats. Each approach is backed by an expanding body of preclinical data and clinical trial evidence that validates the critical role of IL-17A in driving inflammation and underscores the immense potential for therapeutic intervention. With continued innovation, deeper insights into IL-17 signaling, and advances in precision medicine, the field is poised to deliver even safer, more effective, and more convenient treatments for patients suffering from IL-17A–mediated diseases.