A bispecific antibody targeting PD-L1-positive tumors stimulates T cell via 4-1BB
QL301 activates 4-1BB only when concurrently engaged to PD-L1, an immune checkpoint mediator elevated in the immuno-suppressive tumor microenvironment. Unwanted toxicity associated with non-specific activation of 4-1BB is therefore minimized. QL301 blocks the interaction of PD-1 with PD-L1 independent of 4-1BB binding. The combination of 4-1BB activation and PD-L1 blockade promotes a robust and lasting anti-tumor immune response. QL301 was well tolerated in a toxicology study. A phase 1 clinical trial is ongoing.
Selective CD47 targeting to improve therapeutic windows
The ubiquitous expression of CD47 on normal cells, including red blood cells, presents a therapeutic challenge. Systemic targeting of CD47, by either anti-CD47 monoclonal antibodies or SIRPα-Fc fusion proteins, yielded only moderate clinical benefit due to severe adverse side effects, mainly anemia. QLSF has developed a tumor targeted CD47 bispecific antibody with reduced binding to red blood cells while retaining potent phagocytosis of tumor cells in vitro and delayed tumor growth in vivo. QL401 also blocked the PD-L1/PD-1 checkpoint, providing a secondary mechanism of immune reactivation. QL401 was well tolerated in a toxicology study without anemia. A phase 1 clinical trial is expected to start late Q4 2021.
A tumor targeted cytokine fusion with an improved therapeutic window
Cytokines are potent stimulators of the immune system and have long been investigated and used as therapeutics to treat cancer. However, free cytokines have short half-life and the lack tumor targeting often resulted in systemic toxicity. IL-15 is a stimulatory cytokine that shares the common beta and gamma receptors with IL-2. In contrast to IL-2, IL-15 is more selective for NK and effector memory T cells, with less proliferative effect on Tregs, making it a more preferred therapeutic candidate. QL415 is a PD-L1 x IL-15 fusion protein that was designed to enhance tumor accumulation and prolong blood circulation, thereby widening the therapeutic window. QL415 was highly effective in suppressing tumor growth in vivo, in contrast to PD-L1 monoclonal antibody or a non-targeted IL-15 fusion molecule. The follow up tumor rechallenge study showed lasting protective memory. QL415 was tolerated in a toxicology study well above the therapeutic efficacious dose. A phase 1 clinical trial is ongoing.
A bispecific T cell engager targeting both tumor and stromal cells
Simultaneous binding of a T cell bispecific antibody to CD3 on T cell and a tumor cell surface antigen results in the formation of an immune synapse, which leads to activation and proliferation of the T cell and subsequent killing of the tumor cell. T cell bispecific antibody mediated killing of tumor cell does not require pre-existing immunity and may occur independently of T cell specificity, activation, and differentiation status. This allows for re-activation of immune response in poorly immunogenic “cold” tumors.
Unlike conventional T cell bispecific engager, QL315 is uniquely designed to target both the tumor and its stromal components via binding of LRRC15, an antigen shared by both and highly upregulated in several types of solid tumors. QL315 is optimized for specificity and potency by carefully fine tuning the avidity and affinity of both LRRC15 and CD3 targeting moieties. This ensures maximum efficacy while reducing unwanted toxicity for a wider therapeutic window.