Novel Bispecific Immune Synapse Engagers harness potent T cell anti-tumor immunity

Approved checkpoint inhibitors, dominant by anti-PD-1 monoclonal antibodies, are primarily aimed at blocking inhibitory signaling by immune cells and constitute a front-line treatment for many cancer types. However, most patients do not respond to these inhibitors, while others rapidly become resistant. Recent studies suggest that T cell/dendritic cells (DC) crosstalk is essential for the efficacy of anti-PD-1. Here, we show that conventional type 1 DC (cDC1s), a rare DC population within the tumor microenvironment (TME) specialized in cross-presentation and priming of T cells, are essential for effective tumor elimination by anti-PD-1. Temporary depletion of cDC1 at the active phase of anti-PD-1 abrogates the anti-tumor response. We hypothesize that low cDC1 frequency in the TME limits PD1 efficacy and postulate that a reagent that will facilitate specific physical engagement of T cell-DC crosstalk in combination with blocking PD-1 checkpoint signaling may greatly enhance the potency of current immunotherapy treatments. We developed a novel family of cDC1-targeted, PD-1 blocking bispecific antibodies that facilitate T cell-DC immune synapse formation in the TME and term these new reagents Bispecific Immune Synapse Engagers (BiSE). We generated several versions of BiSE, engaging T-DC synapses through different targets, affinities and valencies, and characterized their biochemical properties, their biophysical ability to facilitate T-DC immune synapses, and their PD-1 blocking activity. BiSE treatment results in potent T-cell mediated anti-tumor activity in several pre-clinical models as compared to traditional anti-PD-1 treatment. We suggest BiSE as a novel and highly effective cancer therapy that effectively sensitizes tumors to PD-1 inhibition.