Abstract LB030: SHR-A1921, a novel TROP-2 ADC with an optimized design and well-balanced profile between efficacy and safety

Abstract

Trop-2 is a promising target for ADC therapy due to its high expression in many solid tumors. The approval of Trodelvy, a Trop-2 directed ADC, for the treatment of refractory or drug-resistant triple negative breast cancer (TNBC) demonstrated the therapeutic value of Trop-2-targeted ADC. However, a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea suggests the safety of Trodelvy needs to be improved. Here, we presented a novel Trop2-directed ADC, SHR-A1921, consisting of a topoisomerase I inhibitor (Proprietary payload, SHR9265) conjugated to a proprietary IgG1 mAb via cleavable linkers. SHR-A1921 demonstrated several advantages over other Trop-2 directed ADCs in the field. SHR9265 is a novel exatecan derivative designed by Hengrui with a better liposolubility and cellular permeability. SHR-A1921 had a drug-to-antibody ratio (DAR) of 4. Compared with other Trop-2-targeted ADCs in the field, such as Trodelvy, TINA-SHR79711 (a molecule synthesized using the published structure of DS-1062), and SKB264, SHR-A1921 has considerable advantages as follows: (1) Stronger binding affinity to both human and rhesus macaque TROP-2 than TINA-SHR79711; (2) Improved plasma stability in plasma of different species presumably due to the proper steric hindrance which was purposely designed on the payload for reducing non-intended cleavage; (3) Stronger bystander cell killing effect presumably due to the increased lipophilicity of the payload vs. that of the payload in TINA-SHR79711; (4) Superior in vivo efficacy in a PSCC2 CDX Model (FaDu) with high Trop-2 expression (TGI 101% vs 53% [TINA-SHR79711] @ 1 mpk) and in an ovarian cancer CDX Model (SK-OV-3) with moderate Trop-2 expression (TGI 63% vs. 23% [TINA-SHR79711] @ 3 mpk; 87% vs. 16% [TINA-SHR79711] @ 10 mpk); (5) ≥ 2X longer half-life in patients# vs. SKB264 vs. IMMU-132, supporting more flexible dosing frequency; (6) Lower free toxin/ADC ratio# regarding PK exposure in patients compared with SKB264 (< 1% vs. 5-6%); (7) approximately linear pharmacokinetics profile in patients with T1/2 ranging from 2.5 to 4.5 days. In summary, SHR-A1921 is a novel anti-TROP2-targeted ADC with a high permeable payload and optimized DAR demonstrating great stability and high potency in both in vitro and in vivo studies. SHR-A1921 also showed compelling efficacy and good safety profile from 50+ subjects of Phase I clinical trial in China (NCT05154604). Pivotal phase III trial for NSCLC is planned in China. (Notes: 1. TINA-SHR7971 is a molecule that Hengrui synthesized using the published structure of DS-1062. 2. PSCC: pharyngeal squamous cell carcinoma. #. non-head-to-head comparison.) Citation Format: Ning He, Chunpeng Yang, Yang Yang, Zhendong Xue, Jianyan Xu, Linda Zhao, Jun Feng, Xin Ye, Zhe Zhang, Feng He. SHR-A1921, a novel TROP-2 ADC with an optimized design and well-balanced profile between efficacy and safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB030.

Targeting Trop2 in solid tumors: a look into structures and novel epitopes

“…However, it remains unresolved whether patients with Trop2-positive cancers would benefit from alternative agents targeting other available epitopes, specifically the safe and tumor-specific sites. It’s worth noting that a significant number of anti-Trop2 candidate drugs still have unclear epitope information ( 39 , 40 , 46 , 48 , 60 – 63 ). Therefore, the pursuit to discover more potent Trop2-targeted therapeutics based on novel druggable epitopes and to further investigate the relationship between epitopes and MOAs of anti-Trop2 agents continues to be a crucial avenue for future research.…”

Progress and Innovative Combination Therapies in Trop-2-Targeted ADCs

“…This breakdown releases cytotoxic drugs, which subsequently bind to DNA or microtubule proteins, inducing cell cycle arrest and eventual apoptosis [15]. The advancement of Trop-2-targeted ADCs has seen rapid progress in recent years, with multiple compounds currently undergoing clinical investigation [16][17][18][19]. activating the MAPK signaling pathway and downstream AP-1 to foster cell differentiation and proliferation [13].…”

“…SHR-A1921 comprises a unique topoisomerase I inhibitor, SHR9265, connected to a proprietary IgG1 monoclonal antibody with a cleavable linker [19]. This ADC demonstrates superior binding affinity to human and cynomolgus monkey Trop-2 compared to existing ADCs targeting Trop-2, resulting in enhanced therapeutic effectiveness.…”