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Background T cell-engaging bispecific antibodies (TCE) activate cytotoxic T cells to initiate a tumor antigen dependent anti-tumor response. The development of these highly potent therapeutics can be limited by on target toxicity in normal tissues and cytokine release syndrome. PROBODY ® therapeutics are recombinant protease activated prodrugs that are masked to reduce target engagement in normal tissues but are preferentially active in the tumor microenvironment upon protease-dependent activation. CDH3 (P-cadherin), a member of the cadherin family involved in cell-cell adhesion, is overexpressed in multiple solid tumors including lung and breast. Here we describe the preclinical efficacy and safety of CX-908, a PROBODY® T cell engager (Pb-TCE) targeting CDH3 and CD3.Methods CX-908, a dually masked Pb-TCE targeting CDH3 and CD3, was engineered using PROBODY ® platform technology. Masked and unmasked TCEs were evaluated for on-cell binding and T cell-dependent cellular cytotoxicity in vitro, efficacy in mouse xenograft models, and safety in non-human primate tolerability studies.Results Compared to the unmasked TCE, CX-908 demonstrates at least a 500-fold decrease in target binding in vitro. Similarly, in vitro cytotoxic potency of CX-908 is reduced by at least 1000-fold. However, in vivo, CX-908 potently induces tumor regressions in established breast and lung cancer cell line derived xenograft tumor models. Additionally, studies performed in non-human primates demonstrate that CX-908 is well tolerated with 100-fold improved tolerability compared to the unmasked form and shows significantly reduced cytokine release.Conclusions CX-908 shows strong anti-tumor efficacy and an improved tolerability profile compared to the unmasked TCE in preclinical studies. These data indicate that CX-908 has a wide predicted therapeutic window and support the potential to target CDH3 positive solid tumors clinically.Ethics Approval Rodent studies were approved by the CytomX Therapeutics Institutional Animal Care and Use Committee and non human primate studies were approved by the Institutional Animal Care and Use Committee of Alta Sciences or Inovtiv.