Abstract 2955: Preclinical development of TJ101, a potent bispecific ADC targeting EGFR and B7-H3 for the treatment of solid cancers

Abstract Antibody-drug conjugates (ADCs) have emerged as a promising class of targeted therapeutic agents; however, off-tumor toxicity and drug resistance remain as major challenges. Bispecific ADCs are designed to target two distinct antigens or different epitopes on the same antigen. Compared to monoclonal antibody ADCs, bispecific ADCs can enhance targeting to the tumors that co-express both antigens and reduce the likelihood of off-tumor toxicity. EGFR is a validated cancer therapeutic target that is upregulated in various solid cancers such as lung, head and neck, breast, and kidney cancers. Activation of EGFR through mutation, overexpression, or amplification drives proliferation, survival, and metastasis of tumor cells. The B7 family protein B7-H3, also known as CD276, is widely overexpressed in a range of solid cancers including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck squamous cell carcinoma (HNSCC), prostate cancer, and breast cancer. Notably, B7-H3 expression is limited in normal tissues, making it an attractive target for ADC approaches. Interestingly, EGFR is co-expressed with B7-H3 in the majority of lung cancer and HNSCC cases (TCGA dataset) and in many solid cancer cell lines (DepMap Portal). TJ101 is a bispecific ADC directed against human EGFR and B7-H3. Its backbone is a natural IgG1 format bispecific antibody heterodimerized using knobs-into-holes (KIHs) technology. The affinity of the parental humanized anti-EGFR antibody is reduced to minimize on-target toxicity, while the anti-B7-H3 antibody retains high affinity. The warhead of TJ-101 is PY-4car2, a novel payload derived from camptothecin, conjugated with a cleavable linker. TJ101 exhibited synergistic internalization and cytotoxicity in multiple cancer cell lines expressing EGFR and B7-H3. Inhibition of antigen binding through pre-treatment with parental unconjugated antibody prevented the cytotoxicity of TJ101. TJ101 treatment in NSCLC, HNSCC, and colon cancer CDX models demonstrated potent, dose-dependent anti-tumor activity. Importantly, TJ101 also achieved significantly better anti-tumor activity than monoclonal anti-EGFR or anti-B7-H3 ADCs in EGFR/B7-H3 co-expressing models. Furthermore, single administration of TJ101 produced durable tumor regressions in PDX models derived from NSCLC, SCLC, HNSCC, breast cancer, and esophageal cancer. TJ101 was well-tolerated in a non-GLP toxicity study in cynomolgus monkeys with the highest nonseverely toxic dose (HNSTD) exceeding 30 mg/kg. In summary, TJ101 is a promising bispecific ADC with highly potent anti-tumor efficacy across multiple solid cancer types and preferable toxicity profiles, enabling an increased therapeutic index. Additionally, the dual-targeting approach of TJ101 offers a significant advantage in overcoming potential tumor resistance that may arise during future clinical applications. Citation Format: Li Qi, Shugaku Takeda, Yangxin Zhang, Mao Huang, Dongdong Zhou, Yanli Mao, Zhaoyuan Chen, Siyi Hu. Preclinical development of TJ101, a potent bispecific ADC targeting EGFR and B7-H3 for the treatment of solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2955.