XmAb819 is a tumor-targeted, T-cell engaging XmAb® 2+1 bispecific antibody in development for patients with renal cell carcinoma (RCC). XmAb819 engages the immune system and activates T cells for highly potent and targeted killing of tumor cells expressing ENPP3, an antigen highly expressed on kidney cancers.
ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase 3) is differentially expressed between RCC (high expression) and normal tissues (low expression). In order to attack RCC cells selectively, XmAb819 was engineered as an XmAb 2+1 bispecific antibody with two binding domains against ENPP3 and one cytotoxic T-cell binding domain against CD3, a component of the T-cell receptor (TCR) complex. Xencor’s XmAb Bispecific Fc Domain serves as the scaffold for these binding domains and provides for long circulating half-life, stability and ease of manufacture.
Xencor is conducting a Phase 1 study of XmAb819 in patients with advanced renal cell carcinoma.
XmAb® 2+1 Bispecific Antibodies
T-cell engaging bispecific antibodies with single tumor-antigen binding domains (1+1 formats) cannot always be designed to selectively target tumor antigens, particularly when the antigen is expressed on normal tissues. Limited selectivity for tumor cells may lead to the killing of normal tissues that express the antigen at lower levels, including critical organs, which can cause poor tolerability in clinical testing.
With two tumor-antigen binding domains and one T-cell binding domain, Xencor’s multivalent XmAb 2+1 format enables antibodies to bind more avidly to – and selectively kill – tumor cells with higher antigen density, potentially sparing normal cells. The XmAb 2+1 bispecific antibody format may be a particularly powerful tool for developing drug candidates against solid tumors.