Abstract LB218: Developing a bispecific anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment

Abstract

Abstract Developing a bispecific anti-ROR1 Antibody Drug Conjugate for hematological and solid tumor treatment Receptor tyrosine kinase ROR1 is a type I transmembrane protein belongs to the ROR family members. ROR1 is a receptor for Wnt family signaling molecules Wnt5a and is a key regulator of normal cellular process, including cell proliferation, survival, and migration. It is also involved in the development and progression of many types of cancer. Although being an oncofetal protein with limited expression in most of the normal tissues, ROR1 is expressed abnormally in various hematological and solid cancers, making it a highly attractive target for antibody-drug conjugate (ADC) therapy. The current clinical results of ROR1 ADC have been promising in treating patients with relapsed and/or refractory (R/R) hematologic malignancies. Utilizing our unique and innovated linker platform, we screened many anti-ROR1 ADCs, with defined DAR=4. Those unique ADCs consist of a humanized monoclonal antibody (mAb against single epitope) or a bispecific antibody (BsAb against two epitopes), stably conjugated to an antimitotic agent. The bispecific mAbs that target to two different epitopes of ROR1, are superior to those antibodies that target to single epitope in the binding to ROR1-expressing tumor cells, the induction of tumor cell death and anti-tumor immunity. Our novel linker structure prevents payloads from coming off of the antibody during the circulation, significantly reduced the off-target toxicity. In vitro and In vivo studies demonstrated the antitumor activity of anti-ROR1 ADCs outperformed the lead anti-ROR1 ADC currently in phase II/IIl trial, providing a promising treatment for hematological and solid cancers with a better safety profile and a larger therapeutic window. The lead candidate molecule, BR111A will start the preclinical studies soon. Citation Format: Xiaobei Zhao, Jie Zhu, Zhenhua Wu, Jing Li, yaqiong zhou, Lei Nie, Gang Chen. Developing a bispecific anti-ROR1 antibody drug conjugate for hematological and solid tumor treatment [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 LB218.