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.