An In-Depth Review of MDX-018 (HuMax-Inflam / BMS-986253): A Therapeutic Antibody Targeting Interleukin-8

1. Executive Summary

MDX-018, an investigational therapeutic agent, is a fully human monoclonal antibody specifically designed to target and neutralize interleukin-8 (IL-8), a pivotal chemokine implicated in a spectrum of human diseases. Known by various designations including HuMax-Inflam, HuMax-IL8, BMS-986253, and Adakitug, this antibody has undergone extensive evaluation across a diverse range of clinical indications. These encompass oncological conditions such as glioblastoma, various other solid tumors (including liver cancer and non-small cell lung cancer - NSCLC), and inflammatory disorders like palmoplantar pustulosis, chronic obstructive pulmonary disease (COPD), myelodysplastic syndromes (MDS), and even infectious complications such as those seen in COVID-19.

The primary mechanism of action of MDX-018 involves binding to IL-8, thereby preventing its interaction with its cognate receptors, CXCR1 and CXCR2. This blockade effectively abrogates IL-8-mediated signaling, which is known to drive neutrophil recruitment, sustain inflammation, promote angiogenesis, and contribute to tumor progression and immune evasion.

The clinical development of MDX-018 has been characterized by a complex trajectory, involving multiple pharmaceutical entities including Genmab, Medarex, and Bristol-Myers Squibb. While some therapeutic avenues, such as palmoplantar pustulosis and glioblastoma, have been discontinued despite early promising signals, research and clinical trials have continued or completed in other areas, notably in solid tumors, MDS, and COVID-19. The safety profile of MDX-018 has generally been reported as manageable in several studies, particularly as a monotherapy, although the adverse event landscape becomes more complex when used in combination regimens, aligning with expectations for multi-agent immunotherapies.

The broad spectrum of indications explored for MDX-018 underscores the ubiquitous involvement of IL-8 in diverse pathophysiological processes. However, this breadth also highlights the inherent challenges in translating a single-target therapeutic strategy into widespread clinical success across such varied conditions. The intricate development history, marked by shifts in focus and sponsorship, likely reflects the mixed efficacy signals observed and strategic realignments within the pharmaceutical industry. The future therapeutic positioning of MDX-018, or indeed IL-8 targeting strategies in general, will necessitate a more refined approach, potentially focusing on specific, biomarker-defined patient populations or rationally designed combination therapies to unlock its full potential.

2. Introduction to MDX-018 (HuMax-Inflam / BMS-986253 / Adakitug)

Nomenclature and DrugBank Identification

The investigational drug central to this report is identified by the DrugBank ID DB05484, with MDX-018 being a primary designation [User Query]. Throughout its development and across different research groups and pharmaceutical entities, it has accumulated several aliases. These include HuMax-Inflam [1], HuMax-IL8 [1], BMS-986253 [1], and Adakitug.[6] The existence of multiple names is a common occurrence in pharmaceutical development, reflecting transitions between research phases, sponsoring organizations, or licensing agreements. A comprehensive understanding of these synonyms is vital for accurately tracking the drug's research and clinical history.

Clarification of Drug Type

It is important to clarify a discrepancy noted in the initial information provided for MDX-018. While the "Type" was listed as "Small Molecule" [User Query], this is inaccurate. The background description within the same query, along with extensive data from research sources, consistently and unequivocally identifies MDX-018 as a fully human monoclonal antibody.[1] More specifically, it is an IgG1 kappa (IgG1,κ) antibody.[3] This distinction is fundamental, as monoclonal antibodies possess unique pharmacokinetic, pharmacodynamic, manufacturing, and immunogenic profiles that differ substantially from those of small molecule drugs. The therapeutic approach, mechanism of action, and potential side effects are all intrinsically linked to its nature as a large protein therapeutic.

Development History and Key Stakeholders

The development of MDX-018 has involved several key organizations over more than two decades. It was originated by Genmab A/S, utilizing the UltiMAb® human antibody generation technology from Medarex, Inc..[4] Early development was a joint effort between Genmab and Medarex.[4]

The development pathway subsequently saw licensing agreements and acquisitions. In 2012, Genmab granted an exclusive worldwide license for HuMax-IL8 to Cormorant Pharmaceuticals.[8] Later, Bristol-Myers Squibb (BMS) acquired Cormorant Pharmaceuticals, thereby obtaining the rights to the HuMax-IL8 program, which became known under the BMS designation BMS-986253.[4] Clinical trials for MDX-018/BMS-986253 have been sponsored or conducted by these entities and in collaboration with various academic and research institutions, including the National Cancer Institute (NCI), Icahn School of Medicine at Mount Sinai, and others.[4] This complex lineage of development, involving pioneering biotech firms and large pharmaceutical companies, underscores the long and often convoluted journey of biologic drug candidates from discovery to potential clinical application. The consistent re-emergence of this antibody under various designations and stewardship suggests a persistent scientific and commercial interest in the therapeutic potential of targeting IL-8, despite the evident challenges encountered along its developmental path. The initial nomenclature "HuMax-Inflam" also hints at an early primary focus on inflammatory conditions, with oncological applications likely explored subsequently or in parallel as the understanding of IL-8's multifaceted role in cancer biology expanded.[5]

3. Mechanism of Action and Pharmacodynamics

Target: Interleukin-8 (IL-8/CXCL8) and its Receptors (CXCR1/CXCR2)

MDX-018 is a fully human IgG1,κ monoclonal antibody engineered to specifically target and neutralize human interleukin-8 (IL-8), also known as CXCL8.[1] IL-8 is a potent pro-inflammatory chemokine belonging to the CXC chemokine family. It is produced by a variety of cell types, including macrophages, epithelial cells, airway smooth muscle cells, and endothelial cells, often in response to inflammatory stimuli.[1] IL-8 exerts its biological effects by binding to two distinct G protein-coupled receptors (GPCRs) expressed on the surface of target cells: CXCR1 (IL-8RA) and CXCR2 (IL-8RB).[1] While both receptors bind IL-8, CXCR1 generally exhibits a higher affinity for this ligand compared to CXCR2.[1] The expression of these receptors is prominent on neutrophils but also found on other cell types, including monocytes, endothelial cells, and certain cancer cells.[16]

Molecular Interactions and Inhibition of IL-8 Signaling

Preclinical characterization of HuMax-IL8 (MDX-018) revealed that the antibody binds to a discontinuous epitope on the IL-8 protein. Significantly, this binding site overlaps with the region of IL-8 responsible for docking with its primary receptor, CXCR1.[9] By binding to this critical region, MDX-018 physically obstructs the interaction of IL-8 with both CXCR1 and CXCR2.[10] This steric hindrance effectively prevents IL-8 from activating its receptors, thereby blocking the downstream intracellular signaling cascades that mediate its diverse biological functions.[10] The ability to neutralize the ligand IL-8 itself means that MDX-018 can inhibit signaling through both CXCR1 and CXCR2, offering a comprehensive blockade of the IL-8 pathway. This is a potentially more thorough approach than targeting only one of the receptors, given that both contribute to IL-8's pathological effects.

Pharmacological Effects: Anti-inflammatory, Anti-angiogenic, and Anti-tumor Activity

The neutralization of IL-8 by MDX-018 translates into several key pharmacological effects, forming the rationale for its investigation in inflammatory diseases and oncology:

• Anti-inflammatory Effects: A primary consequence of IL-8 blockade is the inhibition of neutrophil-mediated inflammation. MDX-018 effectively blocks the binding of IL-8 to neutrophils [5] and, as a result, potently inhibits neutrophil activation and their chemotactic migration towards sites of inflammation.[5] This leads to an overall reduction in inflammation.[10] This direct interference with neutrophil trafficking and activation is central to its potential in treating conditions characterized by neutrophilic inflammation.
• Anti-angiogenic Effects: IL-8 is a known pro-angiogenic factor. Preclinical studies demonstrated that HuMax-IL8 can effectively block the formation of new blood vessels (angiogenesis) induced by IL-8 in animal models.[5] This anti-angiogenic property is particularly relevant for its potential application in cancer, where tumors rely on neovascularization for growth and metastasis.
• Anti-tumor Activity: Beyond its impact on angiogenesis, IL-8 blockade by MDX-018 has shown direct and indirect anti-tumor effects in preclinical settings. It has been observed to decrease the proliferation of susceptible tumor cells [10] and affect tumor vascularization in models using primary human tumors grown in immunodeficient mice.[5] Consequently, MDX-018 has demonstrated the ability to inhibit tumor growth in these models.[2] IL-8 itself is recognized for promoting immune escape and tumor progression.[1] Furthermore, there is preclinical evidence suggesting that IL-8 blockade may reduce mesenchymal features in tumor cells, potentially rendering them less resistant to other treatments.[8] This latter effect is significant, as epithelial-to-mesenchymal transition (EMT) is frequently associated with increased tumor aggressiveness and therapeutic resistance.

The inhibition of neutrophil migration and activation is a key mechanism that directly leads to reduced inflammation. In the context of cancer, this can also profoundly impact the tumor microenvironment by diminishing the presence of pro-tumorigenic neutrophils and potentially myeloid-derived suppressor cells (MDSCs), both of which are recruited by IL-8 and contribute to an immunosuppressive milieu.[8]

4. The Role of Interleukin-8 (CXCL8) in Pathophysiology

IL-8 as a Mediator of Inflammation and Immune Response

Interleukin-8 (IL-8), or CXCL8, is a cornerstone chemokine in the initiation and propagation of inflammatory responses. Its most well-characterized function is as a potent chemoattractant and activator for neutrophils, which are typically the first leukocytes recruited to sites of tissue injury or infection.[5] IL-8 expression is rapidly upregulated by various cells in response to pro-inflammatory stimuli, including bacterial products and other cytokines.[37] Once released, IL-8 establishes a chemotactic gradient that guides neutrophils to the inflamed area, where it also induces their degranulation (release of antimicrobial and proteolytic enzymes) and enhances the expression of cell surface adhesion molecules, facilitating their function.[38] Reactive oxygen species (ROS), often generated during inflammation, can further stimulate IL-8 production, potentially creating a positive feedback loop that amplifies the inflammatory cascade.[38] Beyond acute inflammation, IL-8 is implicated in the resolution phase of inflammation and has been noted to play a role in complex psychoneuroimmunological processes, with potential contributions to both neuroprotection and neuroinflammation depending on the context.[37] The critical role of IL-8 in marshalling neutrophil responses provides a clear rationale for its therapeutic targeting in a variety of inflammatory diseases, including those initially considered for MDX-018, such as pustular dermatoses and COPD.

IL-8's Multifaceted Role in Cancer

The involvement of IL-8 extends significantly beyond simple inflammation into the realm of cancer pathogenesis, where it plays a multifaceted, predominantly pro-tumorigenic role. IL-8 is frequently found to be upregulated in a diverse array of cancer cell types, and elevated serum levels of IL-8 often correlate with a poor prognosis in patients with various malignancies.[8]

IL-8 contributes to cancer progression through several interconnected mechanisms:

• Tumor Cell Proliferation and Survival: IL-8 can directly stimulate the proliferation and survival of cancer cells.[10]
• Angiogenesis: It is a potent inducer of endothelial cell proliferation and migration, thereby promoting the formation of new blood vessels (angiogenesis) that supply tumors with nutrients and oxygen.[10]
• Metastasis and EMT: IL-8 can enhance tumor cell motility and invasion, contributing to epithelial-mesenchymal transition (EMT), a process that endows cancer cells with migratory and invasive properties, facilitating metastasis.[1]
• Cancer Stem Cell (CSC) Renewal: IL-8 has been implicated in the maintenance and renewal of cancer stem cells, a subpopulation of tumor cells responsible for tumor initiation, progression, and resistance to therapy.[10]
• Immune Evasion and TME Modulation: One of the most critical roles of IL-8 in cancer is its ability to shape an immunosuppressive tumor microenvironment (TME). It achieves this by recruiting immunosuppressive immune cell populations, notably myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), particularly those with an M2-like, pro-tumor phenotype.[8] These cells actively suppress anti-tumor T cell responses.
• Therapeutic Resistance: The IL-8 signaling axis contributes to resistance against conventional chemotherapy and, increasingly recognized, immunotherapy.[39]

The signaling pathways activated by the IL-8 interaction with its receptors (CXCR1/2) are diverse and include the PI3K/Akt, MAPK, and PLC/PKC pathways, as well as FAK-Src, Rho-GTPases, and JAK/STAT3 signaling cascades. These pathways converge on the activation of numerous transcription factors, prominently NF-κB, which not only mediates many of IL-8’s effects but also can induce further IL-8 expression, creating a positive feedback loop that sustains pro-tumorigenic signaling.[40]

The dual capacity of IL-8 to drive both inflammation and key aspects of cancer progression suggests that its therapeutic blockade with an agent like MDX-018 could offer benefits in inflammation-associated cancers or in mitigating cancer therapy-induced inflammation that might paradoxically support tumor growth. However, the immune system's response to IL-8 modulation is intricate. While chronic IL-8-driven inflammation and the recruitment of MDSCs/TANs are generally detrimental in cancer, neutrophils can, in some circumstances, exert anti-tumor effects. A broad inhibition of IL-8 might therefore have complex, context-dependent outcomes on the overall anti-tumor immune response, potentially explaining some of the variability seen in clinical trial results. Nevertheless, the strong rationale for IL-8's role in creating an immunosuppressive TME by recruiting MDSCs and TAMs [39] underpins the strategy of combining IL-8 blockade with other immunotherapies, aiming to render the TME more permissive to anti-tumor immune attack.

5. Preclinical Evaluation

In Vitro Studies

The foundational preclinical work for MDX-018 (HuMax-IL8) established its specific binding characteristics and functional consequences. In vitro assays confirmed that HuMax-IL8 binds to a discontinuous epitope on the IL-8 protein, which critically overlaps with the IL-8 receptor CXCR1 docking site.[9] This binding interaction was shown to effectively prevent IL-8 from engaging with neutrophils and subsequently block IL-8-induced neutrophil activation and chemotaxis (migration).[5] These studies provided direct evidence of target engagement and the antibody's capacity to neutralize key biological activities of IL-8.

In Vivo Animal Models

The promising in vitro findings were further investigated in various in vivo animal models, covering both oncology and inflammation:

• Oncology Models: In preclinical cancer models, particularly those utilizing primary human tumors xenografted into immunodeficient mice, HuMax-Inflam (MDX-018) demonstrated significant anti-tumor activity. It was shown to inhibit tumor growth 2 and to affect tumor vascularization by blocking IL-8-induced angiogenesis.5 The choice of primary human tumor models, rather than solely relying on established cancer cell lines, is noteworthy as these models are generally considered more reflective of human cancer biology and thus may offer better predictive value for clinical efficacy.
• Inflammation and Hematology Models: In contexts relevant to inflammatory conditions like myelodysplastic syndromes (MDS), preclinical data indicated that inhibition of the IL-8 receptor CXCR2 led to a significant reduction in the proliferation of leukemic cell lines.21 Furthermore, treating MDS CD34+ (progenitor) cell cultures with a neutralizing anti-IL-8 antibody resulted in an improvement in erythroid colony formation, suggesting a potential to ameliorate anemia associated with MDS.21

These collective preclinical results provided a robust scientific rationale for advancing MDX-018 into human clinical trials for a range of cancer types and inflammatory disorders. The observation that IL-8 blockade might reduce mesenchymal characteristics in tumor cells [8] was particularly intriguing, as this pointed towards a potential mechanism for overcoming therapeutic resistance, given that the epithelial-to-mesenchymal transition (EMT) process is often linked to increased tumor aggressiveness and reduced sensitivity to anti-cancer drugs.

6. Clinical Development Program

The clinical development of MDX-018 (variously known as HuMax-Inflam, HuMax-IL8, BMS-986253, and Adakitug) has been extensive, spanning multiple phases and a wide array of therapeutic indications in both oncology and inflammatory diseases. The program's complex history involves several sponsors and collaborators, reflecting both the broad scientific interest in IL-8 as a therapeutic target and the challenges inherent in drug development.

A consolidated overview of key clinical trials is presented in Table 1.

Table 1: Summary of Key Clinical Trials for MDX-018/BMS-986253/Adakitug

NCT ID	Other Identifiers	Phase	Indication(s)	Drug(s) Used (MDX-018 in bold)	Status (as per latest available info)	Key Endpoints/Reported Outcomes (Summary)	Sponsor/Collaborators
NCT00076379	MDX-018, HuMax-Inflam	I/II	Palmoplantar Pustulosis	MDX-018	Completed (Discontinued for indication by BMS)	57% achieved ≥50% reduction in disease activity; sequestered IL-8 in situ 5	Genmab, Medarex
NCT00075990	MDX-018, HuMax-Inflam	I/II	Rheumatoid Arthritis	MDX-018	Unknown/Likely Terminated (Discontinued for autoimmune disorders by BMS 4)	No specific results in snippets	Genmab, Medarex
NCT00605900	HuMax-IL8, ABX-IL8	II	COPD	HuMax-IL8	Completed (Discontinued for indication by BMS 4)	Improved dyspnea; no significant change in lung function 19	Genmab
NCT02450188	HuMax-IL8	I/II	Glioblastoma	HuMax-IL8	Unknown/Likely Terminated (Discontinued for indication by BMS 4)	No specific results in snippets	Genmab
NCT02536469	HuMax-IL8, BMS-986253	I	Metastatic/Unresectable Solid Tumors	BMS-986253	Completed	Safe, well-tolerated up to 32mg/kg; 73% SD; serum IL-8 reduced 8	NCI, BMS
NCT01634859	BMS-986253	I	Solid Tumors	BMS-986253	Unknown status	No specific results in snippets	BMS
NCT02669946	HuMax-IL8, BMS-986253	I/II	Solid Tumors	BMS-986253 + Nivolumab	Unknown status	No specific results in snippets	BMS
NCT03739677	BMS-986253	II	Advanced Melanoma (post PD-1/L1)	BMS-986253 + Nivolumab + Ipilimumab vs. Nivolumab + Ipilimumab	Completed	Did not improve ORR or PFS vs. Nivo/Ipi alone 24	BMS
NCT04123379	BMS-986253	II	NSCLC, HCC (Neoadjuvant)	Nivolumab + BMS-986253 (or CCR2/5-inhibitor)	Completed (Nov 2023 4)	Primary: MPR (NSCLC), STN (HCC) 30	Icahn School of Medicine at Mount Sinai, BMS
NCT04572451	BMS-986253	I	Advanced Solid Tumors, Melanoma	SBRT + Nivolumab + BMS-986253	Recruiting (Reinitiated June 2024 4)	Safety of SBRT with IO agents 8	University of Chicago, NCI, BMS
NCT05148234	BMS-986253, 000356-C	I/II	Myelodysplastic Syndromes (MDS)	BMS-986253 +/- DNMTi (Decitabine/Cedazuridine)	Active, Not Recruiting 21	Phase I: OBD/RP2D, Safety. Phase II: ORR 21	NCI, BMS
NCT04347226	BMS-986253, HuMax-IL8, AAAS9881	II	Severe COVID-19	BMS-986253 vs. Standard of Care	Unknown/Likely Completed (Phase II dev reported 4)	Primary: Time to improvement (7-point ordinal scale) 25	Columbia University, NCI, BMS
NCT04248236	BMS-986253 (SPARK2)	II	Head and Neck Cancer (Neoadjuvant)	Nivolumab + BMS-986253 (or Cabiralizumab)	Active 35	Efficacy and safety	Johns Hopkins University, BMS
NCT03984100	BMS-986253	I/II	Pancreatic Cancer	Combination Immunotherapy incl. BMS-986253	Active 35	Safety and efficacy	Johns Hopkins University, BMS
NCT03634661	ABX-IL8	II	Melanoma	ABX-IL8 + Pembrolizumab	Unknown status	Efficacy and safety 26	Unknown (ABX-IL8 likely MDX-018 or biosimilar)

[4]

Clinical Trials in Oncology

• Glioblastoma (GBM): Glioblastoma was an early focus for Genmab's development of HuMax-Inflam.5 A Phase I/II trial (NCT02450188) was initiated for this indication.41 However, despite this initial interest, AdisInsight later reported that Bristol-Myers Squibb discontinued the development of BMS-986253 for glioblastoma.4 The reasons for discontinuation are not detailed in the provided information but could relate to challenges in demonstrating efficacy in this aggressive and difficult-to-treat brain cancer, potentially compounded by issues such as blood-brain barrier penetration for an antibody therapeutic or the complex, multifactorial nature of GBM biology extending beyond IL-8's influence.
• Solid Tumors (General and Specific Types): MDX-018/BMS-986253 has been evaluated in numerous trials for various solid tumors, both as a monotherapy and in combination regimens. The Phase I dose-escalation trial NCT02536469 investigated BMS-986253 in patients with diverse metastatic or unresectable solid tumors, including chordoma, colorectal cancer, prostate cancer, and others. The antibody was found to be safe and well-tolerated at doses up to 32 mg/kg, with no dose-limiting toxicities observed. While no objective tumor responses were reported, 73% of patients (11 out of 15) achieved stable disease, and a significant reduction in serum IL-8 levels was observed, indicating target engagement.8 Combination strategies have been a key focus. NCT04123379, a Phase II trial, explored neoadjuvant nivolumab plus BMS-986253 (or a CCR2/5 inhibitor) in NSCLC and HCC, aiming to assess pathological response and tumor necrosis, respectively.4 This trial completed in November 2023.4 The NCT04572451 Phase I trial is investigating the combination of stereotactic body radiotherapy (SBRT) with nivolumab and BMS-986253 in patients with advanced solid tumors and melanoma. The study aims to determine safe radiation doses when combined with these immunotherapies and subsequently evaluate preliminary efficacy.4 This trial was briefly suspended but had enrollment reinitiated in June 2024.4 A significant trial in advanced melanoma, NCT03739677, evaluated BMS-986253 in combination with nivolumab and ipilimumab versus nivolumab plus ipilimumab alone in patients whose disease progressed on or after prior anti-PD-1/L1 therapy. The addition of BMS-986253 did not lead to an improvement in overall response rate (ORR) or progression-free survival (PFS) compared to the control arm, although safety profiles were comparable.24 This outcome is particularly noteworthy, suggesting that in this specific setting of immunotherapy-refractory melanoma, IL-8 blockade did not provide additional clinical benefit over dual checkpoint inhibition. The reasons could be multifaceted, including that IL-8 might not be the dominant resistance mechanism in this heavily pretreated "hot" tumor population, or that the specific combination did not achieve the desired synergistic effect. Other oncology trials include studies in head and neck cancer (NCT04248236, SPARK2) and pancreatic cancer (NCT03984100), exploring BMS-986253 in combination regimens.35

Clinical Trials in Inflammatory and Autoimmune Diseases

• Palmoplantar Pustulosis (PPP): Early Phase I/II results for MDX-018 (HuMax-Inflam) in PPP (NCT00076379) were encouraging. Genmab and Medarex reported in 2004 that 57% of patients (16 of 28) who completed the study achieved a 50% or more reduction in disease activity one week after the final dosing. The antibody was shown to sequester IL-8 at the site of inflammation.5 Despite these positive early findings, AdisInsight lists PPP as a discontinued indication for BMS-986253.4 This discontinuation, in light of promising initial data, may stem from various factors not explicitly detailed, such as challenges in later-phase trials, strategic portfolio decisions by BMS, the emergence of more competitive therapies for this non-life-threatening condition, or a benefit-risk assessment that did not favor continued development.
• Chronic Obstructive Pulmonary Disease (COPD): COPD was identified as a possible indication by Genmab in 2007.5 A Phase II pilot study (NCT00605900), likely involving MDX-018 or a closely related variant (ABX-IL8), demonstrated that IL-8 neutralization led to an improvement in dyspnea (a key symptom of COPD) in treated patients. However, no significant differences were observed in objective lung function parameters (e.g., FEV1) or overall health status compared to placebo.19 This suggests that IL-8's role in COPD might be more closely linked to symptom generation through airway inflammation rather than contributing to the irreversible structural lung damage that underpins chronic airflow limitation. Such a profile might position IL-8 blockade more as a symptomatic or exacerbation-reducing therapy rather than a fundamentally disease-modifying one in COPD. This indication was also subsequently listed as discontinued by BMS.4
• Autoimmune Disorders (General) and Rheumatoid Arthritis: An early Phase I/II trial in an undisclosed autoimmune disease showed that 57% of patients achieved a 50% or more reduction in disease activity with HuMax-Inflam/MDX-018.36 However, "Autoimmune disorders" is listed as a discontinued area by AdisInsight for BMS-986253.4 A clinical trial for rheumatoid arthritis (NCT00075990) was registered, but specific results for MDX-018 in this indication are not available in the provided materials.43

Clinical Trials in Other Indications

• Myelodysplastic Syndromes (MDS): The ongoing NCT05148234 (NCI-2021-13966) Phase I/II trial is evaluating BMS-986253, both as a monotherapy and in combination with DNA methyltransferase inhibitors (DNMTis; decitabine and cedazuridine), in patients with MDS.21 The rationale stems from the observation that IL-8 is upregulated in MDS and that preclinical studies indicated benefits from IL-8 blockade, including improved erythroid colony formation and reduced leukemic cell proliferation.21 The trial aims to determine the optimal biological dose (OBD) and recommended Phase II dose (RP2D) in Phase I, and overall response rate (ORR) in Phase II. This study represents a strategy to target the inflammatory bone marrow microenvironment that supports MDS progression and potentially to enhance the efficacy of standard MDS therapies like DNMTis by mitigating IL-8-driven chemoattraction of myeloid-derived suppressor cells.
• COVID-19: Given IL-8's role as a significant inflammatory mediator in the 'cytokine storm' associated with severe COVID-19 33, BMS-986253 was investigated in hospitalized patients with severe disease in the NCT04347226 (NCI-2020-05615) Phase II trial.25 The primary objective was to determine the time to improvement on a 7-point ordinal scale.25 AdisInsight reports Phase II development for COVID-19 infections.4 The outcome of this trial could provide valuable insights into the role of IL-8 in acute severe respiratory inflammation and the potential utility of its blockade.

7. Safety and Tolerability Profile

The safety and tolerability of MDX-018/BMS-986253 have been assessed across numerous clinical trials and diverse patient populations.

• General Tolerability in Early Monotherapy Studies: Early phase trials generally reported MDX-018 as safe and well-tolerated when administered as a monotherapy. In a Phase I study in solid tumors (NCT02536469), treatment-related adverse events (TRAEs) occurred in 33% of patients, predominantly Grade 1. At the highest dose tested (32 mg/kg), two patients experienced Grade 2 fatigue, hypophosphatemia, and hypersomnia. Importantly, no dose-limiting toxicities (DLTs) were observed, and the maximum tolerated dose (MTD) was not reached.8 Similarly, in a Phase I/II trial for an undisclosed autoimmune disease (HuMax-Inflam/MDX-018), no DLTs were reported with doses up to 8 mg/kg; two serious adverse events (SAEs) occurred (syncope, acute myocardial infarction) but were not considered related to the study drug by the investigator.36 In a Phase II study in COPD (ABX-IL8), no significant differences in adverse events were noted between the antibody and placebo groups.19
• Safety in Combination Therapies: When combined with other potent immunotherapies, such as nivolumab and ipilimumab in the NCT03739677 trial for advanced melanoma, the safety profile of BMS-986253 was comparable to that of nivolumab plus ipilimumab alone. Both arms exhibited high rates of TRAEs. Specifically, Grade 3/4 TRAEs in the BMS-986253 plus Nivo/Ipi arm versus the Nivo/Ipi alone arm included diarrhea (9.7% vs 15.8%), colitis (6.5% vs 12.3%), increased alanine aminotransferase (ALT) (8.1% vs 5.3%), increased aspartate aminotransferase (AST) (4.8% vs 5.3%), and increased lipase (6.5% vs 3.5%). One Grade 5 TRAE (death) was reported in each arm.24 This suggests that while MDX-018 did not appear to add excessive unique toxicity, it also did not mitigate the known toxicities of the dual checkpoint inhibitor backbone.
• Ongoing Safety Assessments: The Phase I/II trial in Myelodysplastic Syndromes (NCT05148234) includes safety evaluation and determination of DLTs as primary objectives for its Phase I part.21 Similarly, the Phase II COVID-19 trial (NCT04347226) listed safety and tolerability (AEs graded by CTCAE v5.0) as a secondary objective.25 Specific adverse event data from these ongoing or recently completed studies were not fully detailed in the provided materials.

The consistent finding that the MTD was not reached in early solid tumor dose-escalation studies [8] indicates a good tolerability window for monotherapy. However, the ultimate utility of higher doses would depend on demonstrating commensurate efficacy, especially since target engagement (serum IL-8 reduction) was observed across all dose levels tested in that study.

8. Regulatory Status and Intellectual Property

Global Development Status

MDX-018 (HuMax-Inflam/BMS-986253/Adakitug) remains an investigational agent and has not received regulatory approval for any indication in any jurisdiction. Its development has been marked by strategic shifts. Notably, Bristol-Myers Squibb has discontinued the development of BMS-986253 for several indications that were explored in earlier phases, including autoimmune disorders, glioblastoma, and palmoplantar pustulosis.[4] This is significant given that glioblastoma was an initial focus for Genmab [5], and palmoplantar pustulosis had shown encouraging early clinical results.[5]

Despite these discontinuations, development has continued in other areas. As of recent updates, Phase II trials were active or had recently completed for indications such as COVID-19 infections, liver cancer, non-small cell lung cancer (NSCLC), and squamous cell cancer.[4] Furthermore, Phase I/II trials have been ongoing or recently completed in prostate cancer, various solid tumors [4], and myelodysplastic syndromes (MDS).[21] The varied status across indications reflects the complex process of evaluating a drug's efficacy and safety in different disease contexts and making strategic decisions based on emerging data and the competitive landscape. The discrepancy between early promise for some indications and eventual discontinuation underscores the high attrition rates in drug development.

Intellectual Property

The intellectual property surrounding MDX-018 and its target is multifaceted. Genmab A/S holds patents related to human monoclonal antibodies against IL-8, such as US8105588B2, which specifically covers antibodies like HuMab 10F8 (a clone selected for HuMax-Inflam/HuMax-IL8), their pharmaceutical compositions, and methods of use for treating IL-8 mediated disorders.[15] Such composition of matter and use patents are foundational for protecting the originator's innovation.

Concurrently, the emergence of "research grade biosimilar" versions of Adakitug (another name for BMS-986253) by companies like DIMA Biotech indicates interest from other entities in this molecule or its target.[1] DIMA Biotech has stated that their recombinant antibodies are under patent application [6], which could pertain to specific manufacturing processes, formulations, or novel uses of their biosimilar version. The development of biosimilars, even for an investigational drug, suggests that the IL-8 target and the characteristics of this particular antibody are considered to hold value, potentially for further research or future therapeutic development should the originator's patents expire or development be abandoned for certain applications.

9. Discussion: Therapeutic Potential and Future Outlook

Critical Analysis of Efficacy and Safety Data

The therapeutic journey of MDX-018 has yielded a mixed efficacy profile. Early clinical studies in solid tumors showed disease stabilization in a notable proportion of patients, and promising activity was observed in palmoplantar pustulosis with significant reductions in disease activity.[5] In COPD, the antibody demonstrated an improvement in the subjective symptom of dyspnea.[19] However, these early signals, often from open-label or single-arm studies, have not consistently translated into definitive benefits in more rigorous, controlled settings. A key example is the Phase I/II trial in advanced melanoma (NCT03739677), where the addition of BMS-986253 to the potent combination of nivolumab and ipilimumab failed to improve ORR or PFS.[24] This particular negative result in a "hot" tumor type already treated with robust immunotherapy suggests that, in such contexts, IL-8 blockade might offer marginal, if any, additional benefit, or that IL-8 is not the primary driver of resistance. This contrasts with the potential rationale for targeting IL-8 in "cold" tumors or different cancer types where IL-8-driven MDSC recruitment might be more critical to the immunosuppressive microenvironment.

From a safety perspective, MDX-018 has generally been well-tolerated as a monotherapy in its early clinical evaluations.[8] When used in combination with other immunotherapies, such as checkpoint inhibitors, the adverse event profile becomes more substantial, but often remains comparable to that of the backbone therapy without introducing excessive unique toxicities attributable to MDX-018.[24] The careful management of these combined toxicities is crucial for its application in combination regimens.

Positioning of MDX-018 in Current Therapeutics

The scientific rationale for inhibiting IL-8 remains compelling, given its well-documented roles in promoting inflammation, angiogenesis, tumor progression, and an immunosuppressive tumor microenvironment.[10] However, the clinical translation of this rationale into broadly effective therapies has proven challenging, not only for MDX-018 but also for other agents targeting the IL-8/CXCR1/CXCR2 axis developed by various companies. The overall success for this class of drugs has been limited to date, indicating the biological complexity of effectively modulating this pathway for consistent therapeutic benefit across a wide range of diseases.

Challenges in Development

Several challenges have marked the development of MDX-018. The mixed efficacy signals across different indications and trial designs are primary among these. The strategic discontinuation of development for some initial target indications, such as glioblastoma and palmoplantar pustulosis [4], despite early preclinical or clinical promise, points to hurdles in achieving clinically meaningful and statistically robust outcomes in later-stage trials. The biological complexity of IL-8 itself presents a challenge; its roles can be highly context-dependent, and the presence of redundant inflammatory and oncogenic pathways may limit the impact of single-agent IL-8 blockade in many diseases.

Opportunities and Future Research Directions

Despite the challenges, opportunities for IL-8 targeting, and potentially for MDX-018, may still exist, particularly through more refined strategies:

• Biomarker-Driven Patient Selection: A critical path forward involves the identification and validation of biomarkers to select patient populations most likely to respond to IL-8 blockade. This could include baseline IL-8 levels in serum or the tumor, the density of IL-8 receptor-expressing cells (e.g., neutrophils, MDSCs) in the TME, specific genetic markers, or signatures of IL-8 pathway activation. The ongoing MDS trial (NCT05148234), for instance, incorporates the monitoring of IL-8 levels and evaluation of changes in other cytokines and immune cell compositions, which is a step in this direction.[21] Rigorous biomarker analysis, extending beyond just IL-8 levels to include functional markers of TME modulation (e.g., MDSC reduction, T-cell infiltration changes) in response to MDX-018, will be essential.
• Rational Combination Therapies: Exploring novel combinations beyond standard checkpoint inhibitors could unlock synergistic effects. This might involve pairing IL-8 blockade with agents targeting other chemokine pathways, distinct angiogenesis inhibitors, or specific cytotoxic therapies where IL-8 is known to mediate resistance.
• Niche Indications: Focusing on specific diseases or patient subgroups where IL-8 is unequivocally a dominant pathogenic driver and where existing treatments are insufficient could provide a clearer path to demonstrating clinical value. The ongoing investigation in MDS is an example of such a focused approach.[21]

The development trajectory of MDX-018 exemplifies the arduous and often unpredictable nature of bringing antibody therapeutics from the laboratory to the clinic. Even with a well-characterized target and a sound mechanistic basis, achieving consistent and compelling clinical success requires persistence, adaptive strategies, and an increasingly sophisticated understanding of disease biology and patient heterogeneity.

10. Conclusion

MDX-018 (HuMax-Inflam/BMS-986253/Adakitug) is a fully human monoclonal antibody targeting interleukin-8, a chemokine with significant roles in inflammation and cancer. Its development history has been extensive and varied, involving multiple sponsors and exploration across a wide range of oncologic and inflammatory indications. Preclinical studies and early clinical trials provided initial evidence of its potential to modulate IL-8 activity and impact disease processes, particularly in conditions like palmoplantar pustulosis and by demonstrating disease stabilization in some solid tumor patients.

However, the path to definitive clinical efficacy has been challenging. Development has been discontinued for several initial indications, including glioblastoma and certain autoimmune disorders, likely due to a combination of mixed later-phase efficacy results, strategic portfolio decisions by developers, and the inherent complexities of targeting a pleiotropic cytokine like IL-8. While the safety profile of MDX-018, especially as a monotherapy, appears generally manageable, its efficacy, particularly in combination with other potent agents like checkpoint inhibitors in challenging settings such as advanced melanoma, has not consistently demonstrated superiority over existing regimens.

The future of MDX-018, and indeed the broader field of IL-8 pathway inhibition, will likely depend on the successful identification of specific patient populations who are most likely to benefit, guided by robust predictive biomarkers. Furthermore, rationally designed combination therapies that address complementary resistance mechanisms or synergistic pathways may be necessary. The ongoing clinical trials, such as those in myelodysplastic syndromes, will be crucial in determining if MDX-018 can find a definitive therapeutic role in specific clinical niches where the IL-8 pathway plays a dominant and targetable role in pathogenesis. The journey of MDX-018 underscores the complexities of antibody therapeutic development, where even well-founded scientific rationales require extensive and nuanced clinical validation to translate into patient benefit.

11. References

• User Query
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