Claudin 18.2 and CD3 complex in the presence of Programmed cell death protein 1 (PD-1) blockade (CLDN18.2 x CD3 + PD-1 blockade)

This target profile represents a multi-component therapeutic strategy involving the simultaneous targeting of Claudin 18.2 (CLDN18.2) and CD3, typically via a bispecific T-cell engager, in combination with Programmed cell death protein 1 (PD-1) inhibition. CLDN18.2 is a highly selective lineage-stable marker expressed in the tight junctions of gastric mucosal cells and is frequently overexpressed in various gastrointestinal malignancies, including gastric and pancreatic cancers (Sahin et al., 2008, Clinical Cancer Research). By utilizing a bispecific molecule, CD3-positive T-cells are recruited directly to CLDN18.2-positive malignant cells, triggering a potent cytotoxic response independent of traditional MHC-restricted antigen presentation (Baeuerle et al., 2009, Cancer Research). The addition of PD-1 blockade is a strategic approach to enhance the efficacy of T-cell engagers. PD-1 is an inhibitory receptor that, when bound by its ligands (PD-L1/PD-L2), suppresses T-cell activity and promotes immune evasion by the tumor (Pardoll, 2012, Nature Reviews Cancer). In the presence of PD-1 blockade, the T-cells recruited by the CLDN18.2/CD3 bispecific are shielded from exhaustion signals, potentially leading to more durable clinical responses. This combination is currently being evaluated in clinical trials (e.g., NCT04422236) to address the high unmet need in advanced CLDN18.2-positive adenocarcinoma patients.

Other names

CLDN18.2/CD3 bispecific antibody plus PD-1 inhibitorClaudin 18.2 T-cell engager with PD-1/PD-L1 blockadeCLDN18.2-CD3 BiTE and PD-1 combination therapy

The therapeutic strategy utilizes a bispecific antibody to bridge Claudin 18.2-expressing tumor cells and CD3-positive T-cells, inducing redirected T-cell lysis of the tumor. The concurrent PD-1 blockade prevents the inhibition of these activated T-cells by the PD-1/PD-L1 pathway, thereby sustaining the anti-tumor immune response and overcoming potential T-cell exhaustion within the tumor microenvironment.