Abstract 390P
Background
Targeting pancreatic cancer and gastric cancer, characterized by high expression of Claudin18.2(CLDN18.2), presents a significant challenge due to its prevalent expression in normal gastric tissues.
Methods
To improve the cytotoxicity and safety of targeting CLDN18.2, we isolated a humanized CLDN18.2 fragment of antigen binding (Fab) antibody with high specificity and affinity, along with a 4-1BB scFv antibody featuring a distinct binding epitope that elicits TAA-dependent 4-1BB activation. Subsequently, we developed a bispecific antibody (BsAb, OriA362) by combining these two antibodies within the framework of human IgG1, engineered to lack antibody-dependent cellular cytotoxicity (ADCC)/complement-dependent cytotoxicity (CDC) activity and avoid Fc gamma receptor-mediated activation.
Results
With a slightly stronger CLDN18.2 binding activity and finely-tuned 4-1BB binding affinity, OriA362 demonstrated optimized 4-1BB agonist activity upon cross-linking with tumor cells expressing either low or high levels of CLDN18.2. In MC38-hCLDN18.2 low-expression tumors within human 4-1BB transgenic mice, OriA362 treatment demonstrated superior anti-tumor efficacy and resulted in prolonged survival times at both low (0.5 mg/kg) and high (13.3 mg/kg) doses, compared to other analogs of CLDN18.2/4-1BB BsAb (Givastomig), and CLDN18.2 antibody (IMAB362). Remarkably, even at a low dose of 3.325 mg/kg, OriA362 significantly suppressed the growth of MC38-hCLDN18.2 high-expression tumors (6/6 tumor-free). Tumor rechallenge experiments further demonstrated a sustained immunologic memory and protective phenotype following OriA362 treatment, achieving complete tumor growth inhibition.
Conclusions
OriA362, the CLDN18.2/4-1BB BsAb, showcased a best-in-class potential, exhibiting high anti-tumor efficacy, long-term effectiveness, and a promising safety profile. Its capability to target cancer patients with low CLDN18.2 expression expands its potential impact. These findings highlight OriA362 as a promising candidate for further development in cancer therapy.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.