Agonist antibodies for cancer immunotherapy: History, Hopes and Challenges.

Immunotherapy is amongst the most promising new treatment modalities to arise over the last two decades; antibody drugs are delivering immunotherapy to millions of patients with many different types of cancer. Initial success with antibody therapeutics came in the form of direct targeting or cytotoxic antibodies, such as rituximab and trastuzumab, which bind directly to tumor cells to elicit their destruction. These were followed by immunomodulatory antibodies, that elicit anti-tumor responses by either stimulating immune cells or relieving tumor-mediated suppression. By far the most successful approach in the clinic to date has been relieving immune suppression, with immune checkpoint blockade now a standard approach in the treatment of many cancer types. Despite equivalent and sometimes even more impressive effects in pre-clinical models, agonist antibodies designed to stimulate the immune system have lagged behind in their clinical translation. In this review we document the main receptors that have been targeted by agonist antibodies, consider the various approaches that have been evaluated to date, detail what we have learnt and consider how their anti-cancer potential can be unlocked.