Anti‐KIT monoclonal antibody CDX‐0159 induces profound and durable mast cell suppression in a healthy volunteer study

Abstract

Background Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC‐targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX‐0159, an anti‐KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers. Methods CDX‐0159‐mediated KIT inhibition was tested in vitro using KIT‐expressing immortalized cells and primary human mast cells. CDX‐0159 safety and pharmacokinetics were evaluated in a 13‐week good laboratory practice (GLP)‐compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double‐blinded placebo‐controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX‐0159. Results CDX‐0159 inhibits SCF‐dependent KIT activation in vitro. Fc modifications in CDX‐0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX‐0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX‐0159 led to dose‐dependent, profound suppression of plasma tryptase, a MC‐specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. Conclusion CDX‐0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell‐driven disorders.

Mast cells and tryptase are linked to itch and disease severity in mycosis fungoides: Results of a pilot study

“…Currently, patients with severe itch are treated off-label with substances like aprepitant, naloxone, naltrexone, butorphanol, mirtazapine, gabapentin or thalidomide ( 47 ), with limited success and often marked side effects. Newer directed therapies ( 48 , 49 ) aimed at the inhibition or depletion of skin MCs may help treat pruritus, alongside direct lymphoma targeted therapies ( 47 ).…”

Monoclonal Antibodies in Treating Chronic Spontaneous Urticaria: New Drugs for an Old Disease

“…The KIT receptor pathway is involved in mast-cell differentiation. One dose of Barzolvolimab was able to suppress mast cells in healthy individuals and two RDBCTs (NCT04538794, NCT05368285) are recruiting patients with refractory CSU to assess its efficacy and safety [ 67 , 68 , 115 ].…”

“…Hence, blocking the alarmins pathway could potentially be more efficacious and modify the disease course [ 114 ]. Barzolvolimab, suppressing mast cells, could represent another disease-modifying drug [ 115 ]. Although it is not the purpose of this review, it is necessary to mention that, among biologic drugs, small molecule inhibitors such as remibrutinib (LOU064), a Bruton’s tyrosine kinase (BTK) inhibitor with a potential role in the treatment of CSU, represent an alternative to mAbs [ 133 ].…”

Current and Future Approaches in Management of Chronic Spontaneous Urticaria Using Anti-IgE Antibodies

“…Taking into consideration the extensive range of effects of Bruton's tyrosine kinase, a focus has been placed on developing specific BTK inhibitors for the treatment of different diseases, from malignancies to atopic and chronic inflammatory disorders [60]. Therefore, small-molecule BTK inhibitors, such as fenebrutinib and remibrutinib are currently in stage 2 and 3 clinical trials for chronic spontaneous urticaria [61,62].…”