Engineering and preclinical characterization of tebotelimab
To identify individual antibodies for integration into a bispecific PD-1×LAG-3 DART molecule, novel PD-1 and LAG-3 mAbs were generated and selected based on binding characteristics, biophysical properties and the ability to block their respective receptor/ligand axes relative to clinically validated anti-PD-1 (nivolumab) and anti-LAG-3 (relatlimab) mAbs. Humanized PD-1 sequences from retifanlimab (a clinical-stage anti-PD-1 mAb) and MG14.99 (MacroGenics’ anti-LAG-3 mAb) variable regions were selected and incorporated into a hinge-stabilized IgG4κ tetravalent DART molecule to form tebotelimab (Supplementary Fig. Tebotelimab’s binding kinetics for recombinant human PD-1 or LAG-3 antigens (Extended Data Fig. Tebotelimab demonstrated a dose-dependent functional blockade of the PD-1/PD-L1 axis similar to anti-PD-1 mAb nivolumab as evaluated in reporter models of inhibition of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP-2) activation (Supplementary Fig. 