What MIF inhibitors are in clinical trials currently?

Introduction to MIF and Its Role

Definition and Biological Function of MIF
Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine first identified for its ability to regulate macrophage migration. Beyond its classical role in modulating immune cell mobility, MIF has evolved to be recognized as a key mediator in numerous biological processes. It is constitutively expressed in various tissues – including immune cells, epithelial cells, and endothelial cells – and is released rapidly in response to stress or pathogenic stimuli. MIF exhibits enzymatic activity, particularly its (albeit controversial) tautomerase function, which has provided an innovative high-throughput means for screening potential inhibitors even if the precise physiological substrates remain elusive. This intrinsic enzyme activity, regardless of whether it directly contributes to MIF’s biological functions, has enabled researchers to develop assays that quantify inhibitor binding and potency. In this way, MIF is not just a cytokine but also a “druggable” enzyme, serving as a promising target for therapeutic intervention.

MIF in Disease Pathogenesis
MIF is broadly implicated in the pathogenesis of a variety of inflammatory and autoimmune diseases. Elevated levels of MIF have been documented in conditions such as sepsis, rheumatoid arthritis, inflammatory bowel disease, and even a range of cancers. Its role in disease extends to modulating cytokine production, overcoming glucocorticoid-mediated immunosuppression, and activating key intracellular signaling pathways (e.g., AKT and MAPK). In cancer, for example, MIF has been shown to promote tumor growth through stimulating angiogenesis and inhibiting apoptosis, while in inflammatory diseases it acts upstream of many pro-inflammatory cascades. This dual role – acting both as a cytokine and an enzyme – makes MIF an attractive target for therapeutic inhibition, with the goal of attenuating its multifaceted contributions to disease processes.

MIF Inhibitors

Types of MIF Inhibitors
There are several types of MIF inhibitors currently under investigation, which can broadly be categorized into small-molecule inhibitors and biologics (such as monoclonal antibodies).
• Small-molecule inhibitors – These include compounds designed to bind to the tautomerase active site of MIF. An early example is ISO-1, a benchmark inhibitor used in preclinical studies to block MIF’s tautomerase activity and ameliorate disease pathology. In addition to ISO-1, research has expanded into analogs that possess enhanced binding affinities and improved pharmacokinetic profiles. Although many of these molecules remain in preclinical stages, some candidates like ibudilast (MN-166) are attracting clinical interest because of their ability to inhibit MIF alongside other targets.
• Biologics – Recent efforts have focused on the development of anti-MIF monoclonal antibodies, which neutralize MIF by directly binding the cytokine and preventing its receptor interaction. These antibodies are specifically engineered to block MIF activity systemically and may offer advantages in terms of specificity and safety. One such antibody, Bax69, has emerged as a potential therapeutic candidate and is designed to provide effective neutralization in conditions where MIF-driven inflammation is central.
• Receptor-targeting approaches – In addition to directly targeting MIF, some strategies involve blocking MIF’s receptor interactions. For example, milatuzumab is an antibody directed against CD74, a key component of the receptor complex for MIF. Although milatuzumab is already approved in hematological malignancies, its mechanism of inhibiting the MIF pathway indirectly makes it of interest in the context of MIF modulation.

Mechanism of Action
MIF inhibitors work primarily by binding to specific regions on the MIF molecule or by interfering with its receptor interactions. The small-molecule inhibitors typically target the tautomerase active site found at the interface of the MIF trimers. Even if the catalytic activity is not directly linked to all of MIF’s biological functions, inhibiting this site can disrupt downstream signaling events mediated by MIF’s interaction with its receptor complex (involving CD74 and, at times, CXCR2/CXCR4). In contrast, antibody-based inhibitors like Bax69 neutralize MIF by binding it with high affinity, thereby preventing its interaction with cellular receptors and subsequent signal transduction that leads to pro-inflammatory and pro-tumorigenic activities. The receptor-targeting agents such as milatuzumab block the primary binding partner for MIF, which usually results in the abrogation of the entire MIF signaling cascade. Thus, the overall effect of these inhibitors is a reduction in the production of inflammatory cytokines, attenuation of cell proliferation, and modulation of immune responses – a mechanistic profile that is promising across a spectrum of disease conditions.

Clinical Trials of MIF Inhibitors

Ongoing Clinical Trials
Current efforts to translate MIF inhibitors into clinical use have led to the initiation of early-phase clinical trials, particularly in the area of oncology and immunoinflammatory conditions.
• Bax69, an anti-MIF monoclonal antibody, has entered Phase I/II clinical trials focusing on cancer treatment. This trial aims to assess its safety, tolerability, and potential efficacy in patients with advanced malignancies where MIF is implicated in tumor progression and immune evasion.
• Ibudilast (also known as MN-166), although originally developed and approved for bronchial asthma and particularly known for its neuroprotective and anti-inflammatory properties, has been repurposed in several clinical trials. Ibudilast not only functions as a phosphodiesterase inhibitor but also exhibits MIF inhibitory activity. There are ongoing clinical trials evaluating its efficacy in conditions ranging from amyotrophic lateral sclerosis (ALS) to acute respiratory distress syndrome in COVID-19 patients, thereby reflecting its broad therapeutic potential against MIF-mediated pathology.
• Other potential candidates based on small-molecule MIF inhibition are under preclinical development and are anticipated to enter clinical testing once further pharmacokinetic and safety data are obtained. Despite extensive preclinical work, there is a notable scarcity of clinical-stage small molecules directly targeting MIF aside from ibudilast which is under repurposing initiatives.
• Additionally, trials involving receptor-targeting antibodies such as milatuzumab (targeting CD74) serve as part of the broader strategy to inhibit the MIF signaling axis. While milatuzumab itself is approved in other indications, its evaluation in the context of MIF-driven diseases further increases the repertoire of clinical interventions aimed at mitigating MIF activity.

Phases of Clinical Trials
Clinical trials for MIF inhibitors are currently in the early phases of development.
• Phase I clinical trials primarily evaluate the safety, tolerability, and optimal dosing of these agents. For example, in the case of Bax69, Phase I trials are designed to determine maximum tolerated doses in patients as well as preliminary pharmacodynamic markers that indicate effective MIF neutralization.
• Phase II trials, where applicable, seek to investigate the efficacy of the inhibitors in particular disease contexts. Trials with ibudilast (MN-166), for instance, look at clinical endpoints such as slowing disease progression in neuroinflammatory states or modulating biomarkers of inflammation, which are associated with MIF activity.
• It is important to note that for many potential MIF inhibitors, the clinical trial pathway is being expedited by repurposing strategies. Because ibudilast has already been approved in other indications, its clinical trials in new therapeutic areas benefit from pre-established safety and pharmacokinetic profiles, allowing the emphasis to shift more rapidly towards proof-of-concept efficacy studies.

Key Findings from Trials
While the clinical data are still emerging owing to the early-phase nature of these trials, several key observations have been reported:
• Preclinical studies and early clinical evidence with Bax69 have demonstrated that neutralization of MIF may lead to a reduction in inflammatory markers and tumor progression. Early reports suggest that anti-MIF antibodies can decrease pro-inflammatory cytokine levels and improve immune cell function within the tumor microenvironment.
• For ibudilast, clinical trials have so far indicated that it is well tolerated at doses that achieve desired MIF inhibition, and some studies have reported improvements in clinical endpoints related to neuroinflammation as well as modulation of immune biomarkers. The repurposing of ibudilast in inflammatory and even neurological disorders suggests that its MIF inhibiting properties could be a significant contributor to its therapeutic effects. For instance, Phase II studies evaluating its role in ALS and inflammatory conditions show promise, with secondary endpoints indicating a reduction in pro-inflammatory cytokines that are known to be regulated by MIF.
• Data from receptor-targeting strategies, such as those using milatuzumab, have shown that interfering with the MIF-CD74 axis can modulate the function of macrophages and other immune cells in the tumor stroma, helping to restore a more effective anti-tumor immune response. Although these agents are not exclusively designed as MIF inhibitors, their clinical utility in conditions driven by MIF signaling further supports the therapeutic relevance of targeting this pathway.
• A common feature across these trials is the focus on identifying relevant biomarkers that accurately reflect MIF activity. Biomarkers such as cytokine levels, immune cell profiles, and even imaging metrics of tumor vascularity are being explored as surrogate endpoints to measure the pharmacodynamic impact of MIF inhibitors. This biomarker-driven approach is crucial not only for demonstrating biological activity but also for eventually selecting the appropriate patient populations that might benefit most from MIF-targeted therapies.

Challenges and Future Directions

Current Challenges in MIF Inhibitor Development
Despite the promising prospects, several challenges persist in the development of MIF inhibitors for clinical use.
• A major hurdle is the intrinsic complexity of MIF’s biology. Given that MIF exhibits both extracellular and intracellular functions – and interacts with multiple receptors – inhibition strategies must ensure sufficient blockade of all relevant pathological pathways without causing unintended disruptions in homeostatic immune regulation.
• The variable expression and multifaceted roles of MIF in different diseases mean that a “one-size-fits-all” inhibitor may not be feasible. While high levels of MIF are associated with poor outcomes in some cancers and inflammatory conditions, the precise thresholds and kinetics may vary significantly among patients. This complicates the development of reliable biomarkers and dosing regimens.
• There is also a relative paucity of clinical-stage small molecules directly targeting MIF. While agents such as ibudilast are being repurposed and anti-MIF antibodies like Bax69 have entered early trials, the translation of novel, selective small-molecule inhibitors from bench to bedside has been slower than anticipated. In many cases, the strong reliance on preclinical models that may not fully capture the human pathophysiological context has led to challenges in assay sensitivity and specificity when moving into clinical settings.
• Safety profiles are another area of concern. MIF is widely expressed and affects many cellular processes, so long-term inhibition poses potential risks for immunosuppression or interference in normal cellular functions. Both preclinical toxicology and early-phase clinical trials must therefore carefully evaluate adverse events and off-target effects.

Future Prospects and Research Directions
Looking toward the future, there is significant potential to advance MIF inhibitors on several fronts.
• Novel inhibitor design – Advances in computer-aided drug design, structure-based pharmacophore modeling, and high-throughput screening continue to yield new candidates with improved potency and selectivity. These novel compounds are expected to enter clinical development in the coming years once appropriate preclinical validations are completed.
• Biomarker development – Future research is likely to focus on the identification and validation of robust biomarkers that can predict patient response to MIF inhibitors. The integration of genomics and proteomics may facilitate the discovery of patient-specific MIF expression patterns, ensuring that only those who are likely to benefit receive targeted therapy. This personalized approach could enhance clinical efficacy while minimizing adverse events.
• Combination therapies – Given the multifunctional role of MIF, combining MIF inhibitors with other therapeutic modalities (such as chemotherapy, immunotherapy, or other cytokine blockers) holds promise for synergistic effects. For instance, inhibiting MIF might enhance the efficacy of checkpoint inhibitors in immuno-oncology by modulating the tumor microenvironment. Similarly, combination regimens using ibudilast with other agents for neuroinflammatory conditions are under consideration.
• Expanding the scope of indications – Initially, the clinical trials with MIF inhibitors have primarily focused on cancer and immunoinflammatory diseases. However, emerging evidence suggests that MIF may also play roles in metabolic disorders, neurodegeneration, and even conditions like post-myocardial infarction inflammation. Broadening the scope of clinical indications can accelerate the overall development of the MIF-targeted therapeutic class.
• Optimizing dosing strategies – Future clinical trial designs may incorporate adaptive trial models, which allow for real-time adjustments in dosing based on pharmacodynamic readouts. Such innovative designs could be instrumental in precisely calibrating the level of MIF inhibition required to achieve therapeutic benefit without over-suppressing the immune system.
• Enhanced clinical trial design – With evolving regulatory guidance and improved analytical tools, future clinical trials will likely incorporate detailed pharmacokinetic/pharmacodynamic modeling to better understand the inhibitor’s behavior in vivo. This dovetails with an increased focus on early-phase trials that prioritize establishing a biologically effective dose rather than simply proceeding to maximum tolerated dose escalation.

Conclusion
In summary, the current landscape of MIF inhibitor clinical trials is an evolving field that reflects the broad therapeutic potential of targeting this multifunctional cytokine. At the forefront are agents such as the anti-MIF monoclonal antibody Bax69, which is in Phase I/II clinical trials for cancer, and repurposed agents like ibudilast (MN-166) that are being evaluated in a range of immunoinflammatory conditions including neuroinflammatory diseases and COVID-19-related acute respiratory distress syndrome. These trials represent early steps toward establishing the safety, tolerability, and preliminary efficacy of MIF inhibitors in the clinical setting.

A general perspective is that while MIF plays a central role in the pathogenesis of several diseases ranging from cancer to autoimmune disorders, the complexity of its biology poses challenges that require innovative approaches in drug design, biomarker development, and clinical trial methodology. Specifically, the multifunctional nature of MIF – which encompasses both enzyme activity and cytokine signaling – means that inhibitors must be carefully engineered to avoid interference with physiological processes while effectively dampening pathological signaling. Researchers have responded by exploring both small-molecule inhibitors (e.g., ISO-1 analogs and repurposed ibudilast) and biologics (e.g., anti-MIF antibodies like Bax69), each of which has its own advantages and hurdles.

From a specific perspective, the ongoing clinical trials with Bax69 and ibudilast have provided promising early data; phase I studies are establishing acceptable safety profiles, while phase II results suggest potential efficacy in reducing disease-related biomarkers and improving clinical outcomes. These early successes support ongoing efforts to refine dosing strategies, identify patient populations that may benefit most—and explore combination therapy approaches—to harness the full therapeutic potential of MIF inhibition.

Returning to a general view, the field of MIF-targeted therapy is at the cusp of translating decades of preclinical research into tangible clinical benefits. Although challenges remain—such as achieving sufficient selectivity, establishing reliable biomarkers, and optimizing clinical trial designs—the early-stage clinical data are encouraging. The future research directions lie in developing next-generation MIF inhibitors with refined selectivity and potency, advancing adaptive trial designs, and combining MIF inhibition with other therapeutic modalities to tackle complex diseases more effectively. Ultimately, the successful clinical translation of these strategies could redefine therapeutic paradigms across a wide spectrum of inflammatory, autoimmune, and oncological conditions, thereby fulfilling the promise that MIF inhibition holds for improving patient outcomes.

In conclusion, while the arsenal of MIF inhibitors in clinical trials is still relatively limited—with primary candidates including Bax69 (an anti-MIF monoclonal antibody) and repurposed ibudilast (MN-166) showing encouraging early-phase results—the growing body of supportive preclinical and early clinical data provides a strong rationale for continued investment and research in this field. The integration of advanced drug design, biomarker identification, combination therapy approaches, and innovative clinical trial methodologies is expected to overcome current challenges and pave the way for effective, targeted anti-MIF therapeutics in the near future.