Dual Inhibition of Mast Cells and Thymic Stromal Lymphopoietin Using a Novel Bispecific Antibody, CDX-622.

Abstract

Background: Mast cells (MCs) respond to an array of allergens that drive allergic and inflammatory diseases. Stem cell factor (SCF), the ligand for the receptor KIT, is required for MC survival and function. Thymic stromal lymphopoietin (TSLP) is an alarmin that promotes Type 2 inflammation in asthma and other inflammatory diseases. We describe CDX-622, a bispecific antibody (bsAb), that targets both SCF and TSLP to neutralize these distinct cytokines.

Methods: The bsAb CDX-622 was developed from novel antagonist monoclonal antibodies (mAbs) to SCF (SCF-12) and TSLP (1D10). CDX-622 encodes the full-length 1D10 mAb and the single-chain variable fragment of SCF-12, linked to the C-terminus of the 1D10 heavy chain. CDX-622 was modified to prevent Fcγ receptor interactions and enhance FcRn binding. CDX-622 was tested using in vitro assays of MC and dendritic cell (DC) activation, an ex vivo human skin model, and in vivo studies in nonhuman primates.

Results: Novel SCF and TSLP mAbs with neutralizing activity were generated. The bsAb CDX-622 potently inhibited SCF-driven MC degranulation and TSLP-mediated CCL17 release by DCs. In human skin samples treated with SCF and TSLP, CDX-622 markedly reduced proinflammatory, MC, and DC-related RNA signatures. Additionally, CDX-622 and SCF-12 mAb administered to cynomolgus macaques (Macaca fascicularis) had a profound effect on MCs without any observed toxicity.

Conclusions: CDX-622 is a potent inhibitor of MCs through the neutralization of SCF and effectively blocks Type 2 inflammatory responses driven by TSLP. Dual inhibition of these cytokines may lead to improved clinical outcomes in certain inflammatory disorders.