T cells in the tumor microenvironment require engagement of their T cell receptor (TCR, Signal 1) and their co-stimulatory receptors like CD28 (Signal 2) to achieve full activation. Checkpoint inhibitor therapies reactivate T cells by blocking the receptors that interfere with both these signals, while CD3 T-cell engaging bispecific antibodies strongly activate Signal 1. CD28 is the textbook example of Signal 2 activation; however, the ligands that enhance T cell activation through CD28 are usually not expressed on tumor cells.
CD28 bispecific antibodies are engineered to simultaneously bind to tumor cells and CD28 in order to provide tumor-conditional CD28 signaling. Xencor’s XmAb® CD28 bispecific antibodies are designed to activate CD28 only in the presence of tumor cells, avoiding the superagonist activity that created safety issues for prior CD28 targeting approaches.
XmAb808 is a tumor-selective, co-stimulatory XmAb 2+1 bispecific antibody designed to bind to the broadly expressed tumor antigen B7-H3 and selectively to the CD28 T-cell co-receptor (Signal 2) only when bound to tumor cells, which was demonstrated in in vitro studies. In vivo studies further demonstrated strong potentiation of checkpoint and CD3 cytotoxic activity. Xencor’s XmAb Bispecific Fc Domain serves as the scaffold for the B7-H3 and CD28 binding domains and provides for long circulating half-life, stability and ease of manufacture, and Xencor’s Xtend™ Fc technology further enhances its half-life. XmAb808 is a wholly owned Xencor program.
Xencor is conducting a Phase 1 study of XmAb808 in combination with pembrolizumab in patients with advanced solid tumors.
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.