HLX-58

None of the antibody-drug conjugates (ADCs) targeting Claudin 18.2 (CLDN18.2) have received approval from regulatory authorities due to their limited clinical benefits. Leveraging the radiosensitizing ability of Deruxtecan (DXd) and the internal radiation therapy of ¹³¹I for tumors, we aimed to develop the first radio-antibody-drug conjugates (RADCs) for the treatment of gastric cancer.

The CLDN18.2-specific antibody HLX58 was conjugated with the payload DXd through a cleavable maleimide glycynglycyn-phenylalanyn-glycyn (GGFG) peptide linker. HLX58-Der was labeled with ¹³¹I to produce RADC-¹³¹I-HLX58-Der. HLX58 was labeled with ¹²⁵I for imaging CLDN18.2-positive tumors, providing a reference for RADC treatment in solid tumors. The antigen-binding properties and biodistribution of the RADC were studied both in vitro and in vivo. The cytotoxic effects of the RADC were evaluated in CLDN18.2-positive tumor cell lines and xenografts.

HLX58 was successfully conjugated with DXd using the cleavable maleimide GGFG peptide linker and labeled with ¹³¹I to produce RADC-¹³¹I-HLX58-Der. HLX58 was labeled with ¹²⁵I for imaging CLDN18.2-positive tumors. Both ¹²⁵I-HLX58 and ¹³¹I-HLX58-Der exhibited significant binding affinity for the CLDN18.2-positive cancer cell line. The cytotoxic effect of ¹³¹I-HLX58-Der was observed in the CLDN18.2-positive cell line, with an IC₅₀ of 11.28 ng/mL. In terms of cytotoxicity, ¹³¹I-HLX58-Der exhibited greater activity compared to HLX58-Der. ¹²⁵I-HLX58 and ¹³¹I-HLX58-Der demonstrated similar biodistribution profiles in CLDN18.2-positive tumor models, achieving 5.72 ± 0.41%ID/g (48 h) and 5.83 ± 0.41%ID/g (72 h) in the tumor tissues postinjection, respectively. The average tumor size in groups treated with ¹³¹I-HLX58-Der and HLX58-Der was reduced by factors of 12.15 and 4.80, respectively, compared to the control group. ¹³¹I-HLX58-Der demonstrated no toxic effects on hepatorenal function, routine blood tests, or major organs in mice when compared to the control group.

These findings validate the potential of RADCs targeting CLDN18.2 in treating CLDN18.2-expressing solid tumors.