ES101 is a first-in-class tetravalent bispecific antibody targeting 4-1BB and PD-L1. Its mechanism of action is unique as 4-1BB activation is dependent on PD-L1 binding.
4-1BB is a T cell co-stimulatory receptor and is a compelling immune checkpoint target with proven tumor killing activity in patients once activated. Although 4-1BB targeting antibodies are being developed by multinational companies, however they exhibit dose-dependent liver toxicity in clinical trials and thereby limit dose-escalation and ultimately their efficacy.
While most bispecific antibodies use each arm to target a different antigen, ES101 contains two identical arms that each target both antigens. The structure allows each arm to bind PDL1 on tumors and 4-1BB on T cells simultaneously. Once ES101 binds PD-L1 on tumor cells, its 4-1BB-binding domains drive 4-1BB molecules to cluster on nearby T cell surfaces, a requisite for activating the T cell co-stimulation pathway. This allows focused 4-1BB activation to T cells that are engaging tumors, which lowers the potential for off-target toxicity, and provides both co-stimulatory signaling and checkpoint blockade. Furthermore, to improve tumor targeting, the molecule was also designed to have 10x higher binding affinity to PD-L1 than 4-1BB.
Hence in one design ES101 achieves three things:
1. Preferentially target tumor cells through PD-L1 binding
2. "Release brake" by blocking PD-L1
3. "Provide gas" by activating T cells through PD-L1 binding dependent 4-1BB activation
ES101’s activity was proven to be far superior to the currently marketed PD-1 or PD-L1 antibodies in various functional studies in both cell-line and animal models. Recently, ES101 has entered phase I clinical trials in both US and China.
ES101, also called INBRX-105, was developed by Inhibrx. Elpiscience has Great China rights to the compound, while Inhibrx holds U.S. and other global rights.