Tumor infiltrating lymphocytes express multiple immune checkpoints and co-stimulatory receptors. Xencor’s bispecific tumor microenvironment (TME) activators seek to more effectively reactivate these tumor-killing T cells by engaging multiple T-cell targets simultaneously. This approach eliminates the need for the multiple antibodies and allows for more selective targeting of T cells with high checkpoint expression, which may potentially improve the therapeutic index of combination immunotherapies.
Vudalimab is a bispecific antibody that simultaneously targets immune checkpoint receptors PD-1 and CTLA-4 and is designed to promote tumor-selective T-cell activation. Xencor’s XmAb® Bispecific Fc Domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on vudalimab. XmAb bispecific Fc domains have been engineered to eliminate Fc gamma receptor (FcγR) binding, with the intent to prevent activation and/or depletion of T cells via engagement by FcγR-expressing cells. In preclinical studies, dual blockade of PD-1 and CTLA-4 with vudalimab significantly enhanced T cell proliferation and activation, and anti-tumor activity in vivo.
Xencor has initiated a Phase 2 clinical study of vudalimab in patients with mCRPC, as a monotherapy or in combination depending on molecular subtype, and a Phase 2 clinical study enrolling patients with clinically defined high-risk mCRPC.
New Phase 1b/2 Clinical Study of Vudalimab for First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer
Xencor plans to evaluate vudalimab as a first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC). Multiple responses were observed in checkpoint-experienced, heavily-pretreated patients with mNSCLC in the Phase 1 study of vudalimab.
Part 1 of the new Phase 1b/2 study would randomize patients at one of two doses of vudalimab, in combination with chemotherapy. The study’s second part would randomize patients to either vudalimab plus chemotherapy or pembrolizumab plus chemotherapy. The primary outcome measure of Part 2 would be a comparison of progression-free survival. Xencor anticipates initiating the study by the end of 2023.