116 (PB106) - Preclinical activity for TPX-4589 (LM-302), an antibody-drug conjugate targeting tight junction protein CLDN18.2 in solid tumors

Abstract

Background: Claudin 18 isoform 2 (CLDN18.2) is a tight junction protein involved in the regulation of epithelial cell permeability, barrier function, and polarity. In healthy tissue, CLDN18.2 is selectively expressed in tight junctions of gastric epithelial tissue and hence largely inaccessible to intravenous antibodies. On malignant transformation, CLDN18.2 is exposed on the cancer cell surface and expressed in many solid tumors, including gastric cancer (GC) and pancreatic cancer (PC). CLDN18.2 expression is associated with tumor pathogenesis, proliferation, and metastasis, making it a promising target for cancer therapies. TPX-4589, a novel antibody-drug conjugate (ADC) coupled with cytotoxic payload monomethyl auristatin E (MMAE), was developed to target CLDN18.2. Materials and methods: Preclinical studies were conducted to characterize TPX-4589 in CLDN18.2-positive cells, including binding affinity, antibody-dependent cell-mediated cytotoxicity (ADCC), cell proliferation inhibition, and in vivo efficacy in gastric and pancreatic tumor models. Results: TPX-4589 bound to endogenous CLDN18.2 GC GAXC031 cells in a dose-dependent manner, with an EC50 of 47.25 nM. Internalization was shown in both high- and low-expressing CLDN18.2-positive cells, with superior internalization when compared to zolbetuximab, a monoclonal antibody (mAb) that specifically binds to CLDN18.2 (table). TPX-4589 showed strong concentration-dependent ADCC activity, with EC50 of 0.11 nM, and inhibited tumor cell proliferation in vitro with nanomolar potency in GAXC031 and PC MIA PaCa2-high CLDN18.2 cell lines. In a cell-line xenograft GC tumor model with high CLDN18.2 expression, TPX-4589 significantly reduced tumor volume in a dose-dependent manner and demonstrated superior efficacy to zolbetuximab. In a CLDN18.2-high patient-.derived xenograft (PDX) PC tumor model, increasing doses of TPX-4589 demonstrated superior tumor growth inhibition compared to gemcitabine and LM-102, a compound with identical anti-CLDN18.2 mAb component as LM-302, and similar efficacy to LM-102 + gemcitabine in combination. In a PDX PC tumor model with low CLDN18.2 expression, TPX-4589 showed potent inhibition of tumor growth.Table(abstract: 116 (PB106)). TPX-4589 internalization in CLDN18.2-positive cellsCell lineTPX-4589 (LM-102 conjugated with MMAE)LM-102 (CLDN18.2 mAb)ZolbetuximabControl hIgG1EC50 (nM)CLDN18.2/MKN45.#1(low CLDN18.2 expression)22.44.8NANAEC50 (nM)CLDN18.2/MKN45.#14(high CLDN18.2 expression)3.53.583.93NA Open table in a new tab Conclusions: TPX-4589, a novel CLDN18.2-targeting ADC, showed potent inhibitory effects on tumor cell proliferation in vitro and reduced tumor volume in both high- and low-expressing CDLN18.2 tumor models, with superior internalization and efficacy to zolbetuximab in a GC tumor model. These data suggest that TPX-4589 is a promising therapeutic candidate that warrants further investigation in clinical studies. Conflict of interest: Ownership: Stephanie Correia, Laura Rodon Turning Point Therapeutics Employee and Stock or Stock Options Other Substantive Relationships: Laura Rodon Turning Point Therapeutics Patents planned, issued or pending Yifan Li: Nothing to disclose Zhifang Liu: Nothing to disclose Runsheng Li: Nothing to disclose Yuan Li: Nothing to disclose Wentao Huang: Nothing to disclose