Abstract 3134: SDP03923-000-9106, a novel and optimized LIV-1 ADC with superior anti-tumor efficacy in breast cancer xenograft models

Abstract

Abstract Background: LIV-1, also known as SLC39A6 or ZIP6, is a transmembrane protein belonging to the zinc transporter family. LIV-1 is a promising target for antibody-drug conjugate (ADC) therapy due to its broad expression in tumors and limited normal tissue expression. Ladiratuzumab vedotin, a LIV-1 targeting ADC with payload of MMAE, is now in phase I clinical trial stage and is the only LIV-1 ADC under clinical development worldwide. The preliminary clinical results demonstrated promising efficacy in TNBC (ORR=32%) but no response in HR+/HER2- breast cancer (ORR=0%), and typical MMAE-related adverse events were observed. Herein, we presented a novel LIV-1 directed ADC, SDP03923-000-9106, consisting of a LIV-1 mAb developed in house conjugated to a proprietary topoisomerase I inhibitor via a cleavable linker with an optimized average drug-to-antibody ratio (DAR) of 6. Method: The in vitro binding affinity of SDP03923-000-9106 against LIV-1 protein was measured by Surface Plasmon Resonance (SPR) assays. The expression levels of LIV-1 in different cancer cell lines were detected by flow cytometry and IHC staining. In vitro activity against cancer cell lines was analyzed by CellTiter Glo assays following 10 days of treatment. The in vivo anti-tumor activities were investigated in both CDX and PDX models of breast cancer. Results: SDP03923-000-9106 is a novel anti-LIV-1 ADC comprised of a humanized LIV-1 monoclonal antibody conjugated to the potent topoisomerase I inhibitor (a novel exatecan derivative designed by Hengrui with a better liposolubility and cellular permeability) by a cleavable linker. SDP03923-000-9106 had an optimal drug-to-antibody ratio (DAR) of 6 and showed strong binding affinity to LIV-1 and favorable internalization. SDP03923-000-9106 exhibited robust anti-tumor activity in cell lines across breast cancer, esophageal squamous cancer, gastric cancer, prostate cancer and non-small cell lung cancer. In the LIV-1 highly expressed breast cancer cell line of MCF-7, SDP03923-000-9106 demonstrated a strong inhibitory effect with IC50 of 5.36 nM. Moreover, in a LIV-1 high-expressing patient-derived xenograft model of breast cancer, SDP03923-000-9106 showed pronounced tumor regression at both doses of 3 and 10 mg/kg and showed stronger anti-tumor activity (TGI: 109%) at the same dose of 3 mg/kg versus BMK-MMAE (TGI: 75%; BMK-MMAE is synthesized by Hengrui using the published structure of Ladiratuzumab vedotin). Conclusion: In summary, SDP03923-000-9106 is a novel LIV-1 targeted ADC with a highly permeable payload demonstrating great anti-tumor activity across multiple types of tumors in preclinical studies. The promising preclinical data support advancing SDP03923-000-9106 into clinical testing, and Investigational New Drug (IND) application to NMPA has been submitted. Citation Format: Yanling Gong, Xing Sun, Changyong Yang, Simeng Chen, Wei Zhang, Cheng Liao. SDP03923-000-9106, a novel and optimized LIV-1 ADC with superior anti-tumor efficacy in breast cancer xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3134.