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 it allows for more selective targeting of T cells with high checkpoint expression, which may potentially improve the therapeutic index of combination immunotherapies.
XmAb841 (XmAb22841) is a bispecific antibody that simultaneously targets immune checkpoint receptors CTLA-4 and LAG-3 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. 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, the blockade of CTLA-4 and LAG-3, with XmAb841, and PD-1, with an anti-PD1 antibody, significantly enhanced T cell proliferation and activation, and anti-tumor activity in vivo.
Each of Xencor’s three bispecific TME activators tests a distinct mechanism of TME activation. XmAb717 and XmAb104 are also being evaluated in Phase 1 clinical studies.