Optimizing anti-4-1BB agonistic antibodies for cancer immunotherapy

Immune checkpoint blocking antibodies have gained great success in the clinic however, these treatments are effective for only about 30% of patients. Most of these antibodies block co-inhibitory molecules like PD-1 and CTLA-4 but the development of agonistic antibodies against co-stimulatory molecules has lagged behind. One such co-stimulatory molecule, 4-1BB, activates T cells and promotes anti-tumor immunity upon binding to its ligand, 4-1BBL. Despite the better or equivalent anti-tumor activity in preclinical models compared with anti-PD-1 antibodies, anti-4-1BB antibodies have struggled in clinical trials due to low efficacy and severe liver toxicity.

To investigate the liver toxicity and efficacy issues Dr. Xuanming Yanā€™s group from Shanghai Jiao Tong University employed a mouse model of cancer immunotherapy using Bio X Cellā€™s anti-mouse 4-1BB clones 3H3 and LOB12.3. The authors found that the 3H3 clone induced liver toxicity while the LOB12.3 clone did not. Further, while the 3H3 clone exhibited strong anti-tumor activity independent of FcĪ³R engagement the LOB12.3 clone required FcĪ³R-crosslinking to activate 4-1BB signaling and induce anti-tumor activity. Overall, the authors concluded that strong agonistic antibodies, like 3H3, that can activate 4-1BB in the absence of FcĪ³Rs have the potential to induce liver toxicity, whereas weak agonistic antibodies, like LOB12.3, that require FcĪ³R crosslinking for 4-1BB activation, do not induce liver toxicity, and maintain anti-tumor efficacy.

To extend these results Dr. Yanā€™s group developed a novel anti-human 4-1BB antibody with weak agonistic activity and an engineered Fc region with selective FcĪ³R binding. Compared with the standard anti-human 4-1BB antibodies, Urelumab and Utomilumab, currently in clinical trials, the new antibody showed robust tumor control ability in a wide range of dosages and importantly, it did not induce liver toxicity.

See the complete article in Nature: https://www.nature.com/articles/s41467-019-10088-1