Abstract LB425: A tumor microenvironment-targeting CD98-directed ADC confers robust anti-tumor activity in multiple cancers with favorable pharmacokinetics and safety profiles in preclinical models

Abstract CD98, a subunit of the LAT1/CD98 amino acid transporter complex, is intimately involved in cell adhesion, migration, proliferation, and signal transduction by enhancing amino acid transport and amplifying integrin signaling. CD98 is expressed at aberrantly high levels in many solid tumors and hematological malignancies, and this is frequently associated with poor prognosis, highlighting its potential as a cancer therapy target. However, CD98 is also expressed in various normal tissues hence complicating the development of antibody-based therapies owing to lack of tumor selectivity, poor pharmacokinetics (PK), and safety issues. We previously reported a pH-dependent anti-CD98 monoclonal antibody (mAb) that selectively targets the acidic tumor microenvironment (Tian, X., et al. Nat Biomed Eng 7(1): 8-23.). In the present report, we further developed that mAb into an antibody-drug conjugate (ADC; HH018-sesutecan), in which the mAb is conjugated to a topoisomerase I inhibitor-based linker-drug, sesutecan, at a drug:antibody ratio (DAR) of approximately 8. Sesutecan previously demonstrated promising characteristics in preclinical studies with multiple targets and conferred an encouraging benefit:risk profile in the clinic with a FRα-directed ADC (rinatabart sesutecan). HH018-sesutecan exhibited similar pH-dependent binding as its parental mAb in vitro, and markedly improved PK compared to the non-pH-dependent ADC control in CD98-humanized C57BL/6 mice. HH018-sesutecan demonstrated potent cytotoxicity against CD98-expressing cancer cell lines, strong bystander effect, as well as dose-dependent anti-tumor activity in mouse models representing multiple tumor types (colorectal cancer, ovarian cancer, renal cell carcinoma, lymphoma, hypopharyngeal carcinoma, and oral adeno-squamous carcinoma). Notably, sustained tumor regression was achieved with a single dose of 3-5 mg/kg in ~8 tumor models. A pilot toxicity study was conducted for HH018-sesutecan at two repeat-dose of 30 mg/kg in cynomolgus monkeys. HH018-sesutecan was well-tolerated with the principal toxicity (myelosuppression) being payload driven and reversible, accompanied with a favorable PK profile (half-life of 7-9 days). In summary, our studies demonstrate that the pH-dependent CD98-directed HH018- sesutecan exerts wide-ranging and potent anti-tumor efficacy, as well as favorable PK and safety profiles in preclinical models. HH018-sesutecan is a promising agent for further development in a broad range of CD98-expressing tumors. Citation Format: Fang Yang, Lei Wang, Xinxin Tian, Xuan Qiu, Jianhe Chen, Wenke Qi, Guangyu Li, Haidong Liu, Juan Liu, Suping Huang, Bin Ye, Qilin Wu, Baiteng Zhao, Wenhui Li, Jianhua Sui, Zhu Chen. A tumor microenvironment-targeting CD98-directed ADC confers robust anti-tumor activity in multiple cancers with favorable pharmacokinetics and safety profiles in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB425.