Dual targeting of mast cells and TSLP with a bispecific antibody

Abstract Rationale: Reduction of mast cells (MCs) through stem cell factor (SCF) neutralization combined with inhibition the alarmin TSLP in a single molecule may result broader efficacy inflammatory disorders. Methods: Monoclonal antibodies (mAb) separately targeting SCF and were generated from immunized mice. A potent neutralizing antibody against each target was selected humanized. Bispecific tetravalent (bsAbs) specificity towards generated. Candidate bsAbs tested vitro for activity evaluated pilot non-human primates (NHP) studies. Results: We discovered novel anti-SCF mAb (SCF-12) that potently inhibits SCF-dependent KIT phosphorylation SCF-enhanced degranulation primary human MCs. Separately, anti-TSLP (1D10) receptor binding TSLP-dependent TARC release monocyte-derived DCs. combining humanized SCF-12 1D10 good expression, biophysical profile robust Following demonstration MC depletion NHPs SCF-12, we conducted NHP study two lead candidate bsAbs. Pharmacokinetic, pharmacodynamic tolerability data this will be presented. Conclusions: x successfully neutralize soluble SCF, leading to reduction NHP, TSLP, key implicated autoimmune Combined these pathways using broad utility multiple Celldex Therapeutics