Abstract A127: A novel Integrin beta-6-targeted antibody-drug conjugate featuring a topoisomerase I inhibitor, PBX-004 with potent antitumor activity in multiple preclinical solid tumor models

Abstract Integrins are heterodimeric transmembrane proteins that mediate cell adhesion and signal transduction between cells and the extracellular matrix (ECM). Integrin beta-6 (ITGB6) forms the αvβ6 integrin, which is mainly expressed on epithelial cells and is highly overexpressed in various solid tumors. High ITGB6 expression is associated with poor prognosis in cancers such as colorectal cancer (CRC), non-small cell lung cancer (NSCLC), gastric cancer (GC), and cervical cancer (CC). ITGB6 promotes tumor progression, invasion, and metastasis by activating pathways involved in epithelial-mesenchymal transition (EMT) and cancer cell migration. PBX-004 is a novel antibody-drug conjugate (ADC) consisting of an integrin β6 (ITGB6)-targeting antibody conjugated to a potent Topoisomerase I (TOP1) inhibitor payload. The antibody component of PBX-004 exhibits enhanced binding characteristics to ITGB6 compared to Sigvotatug, a previously studied anti-ITGB6 antibody. This improved specificity was confirmed through comparative binding assays, demonstrating that PBX-004’s antibody shows stronger and more selective affinity toward ITGB6-expressing cells while minimizing off-target interactions. In preclinical studies, PBX-004 demonstrated in vitro efficacy across cell lines with varying levels of antigen expression, including solid tumors such as NSCLC, head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and pancreatic cancer (PC). PBX-004 demonstrated marked tumor regression in Integrin beta-6 overexpressing cell line-derived non-small cell lung cancer (NCI-H441) and pharyngeal carcinoma (Detroit562) xenograft mouse models. The anti-tumor activity of PBX-004 was comparable to, or exceeded, that of the MMAE-based ADC Sigvotatug Vedotin (SGN-B6A; Pfizer/Seagen) at equivalent dose levels. A non-GLP toxicology study in non-human primates (NHPs) is currently underway to further characterize its suitability for clinical development. PBX-004 demonstrated a favorable safety profile in the ongoing non-human primate toxicity study, with no significant toxicity observed up to 15 mg/kg administered every 3 weeks for 3 doses. These findings suggest that PBX-004 may offer a therapeutic window more than 2.5 times greater than that of SGN-B6A (6 mg/kg every 3 weeks for two doses), supporting its potential as a safer and more flexible therapeutic option. Leveraging a camptothecin (CPT)-based payload, PBX-004 demonstrated improved safety over SGN-B6A and the potential to treat both taxane-naïve and taxane-refractory patients. Enhanced efficacy is anticipated through a next-generation antibody and the novel PBX-7016 payload. PBX-004 may overcome the limitations of MMAE-based ADCs and offer a superior option for patients with various integrin beta-6–expressing solid tumors, including NSCLC, HNSCC, and TNBC. Citation Format: DOO YOUNG JUNG, AREUM GO, YOUNGHWA CHUN, BYEONG SUNG LEE, SOHUI KWEON, HYEMIN HAN, SEUNGGUN SHIN, JAEHYEON LEE, SUHYUN PARK, HA YOUNG LEE, Gangadhar Rao Mathi. A novel Integrin beta-6-targeted antibody-drug conjugate featuring a topoisomerase I inhibitor, PBX-004 with potent antitumor activity in multiple preclinical solid tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A127.