Combination of Anti TNFα Agents with Agonistic Anti 4-1BB Antibodies for Treatment of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the digestive tract. Anti-TNFα agents have been successfully applied in the clinic. However, not all patients will respond to anti-TNFα therapy to begin with, and a significant number of patients will experience a secondary loss-of-response to the treatment.

4-1BB is a member of the tumor necrosis factor receptor family and it is a co-stimulatory immune checkpoint. As a multifunctional modulator of immune activity, 4-1BB has become a promising target in cancer immunotherapy. Surprisingly, agonistic antibodies to 4-1BB can also alleviate autoimmune diseases, presumably by induction of activation and proliferation of regulatory T cells (Tregs). Tregs can potentially suppress the activation of immune cells that are involved in the intestinal inflammation.

Combination therapy (CT) for IBD may improve the outcome of the treatment. The goal of our study was to test whether CT of anti TNF-α agents with anti 4-1BB antibodies outperforms the monotherapies in a mouse DSS-colitis model. The motivating rational for the CT was to reduce the severity of intestinal inflammation by combining two orthogonal anti-inflammatory mechanisms: the first mechanism is to reduce the levels of TNF-α, and the second mechanism is to increase the number of Tregs. Our results suggest that there is an advantage to the CT over the monotherapies in several clinical parameters that were evaluated to assess the severity of the colonic inflammation, such as body weight, colon length, histopathology score and disease activity index.