Dual targeting of mast cells and TSLP with a bispecific antibody

Abstract

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