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YH012 is a HER2 x TROP2 bispecific ADC developed using our RenLite platform, which are intended for the treatment of solid tumor. Tumors are killed through specific identification of tumor cells and induction of drug endocytosis. The bispecific antibody backbone is produced by RenLite mice of fully human antibodies with a common light chain. It has a monoclonal antibody structure, which makes purification and drug conjugation easy. The conjugated drug is vcMMAE with a DAR value of 4. YH012 is currently CMC stage.

Preclinical studies have shown the following findings:

1. YH012 identifies tumor cells with HER2 and TROP2 co-expressed, which reduces the potential to attack normal tissue cells, thereby reducing side effects and improving the safety. Meanwhile, the two targets result in a synergy effect.

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Figure 1. An in vitro study showed good selectivity and drug delivery and killing ability of YH012

2. YH012 has good in vivo efficacy in mice

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Figure 2. An in vivo study showed a good inhibitory effect of YH012 on tumor growth in cell line-derived non-small cell lung cancer and ovarian cancer

3. Anti-HER2 x TROP2 BsAb exhibits greater endocytosis than the parental monoclonal antibodies.

4. YH012 is characterized by a simple structure and good stability, which greatly improves the CMC efficiency. Light chain mismatches can be prevented in RenLite mice; and heavy chains are assembled with the knob-into-hole (KIH) technology.

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Figure 3. YH012 has good stability

HER2 is an oncogene that was identified early. It belongs to the human epidermal growth factor receptor family. It contains no ligand binding domain but can bind to its ligand tightly. Overexpressed HER2 forms heterodimers with other family members that have ligands, including EGFR, HER3 (ErbB3) and HER4 (ErbB4), which leads to phosphorylation of the tyrosine kinase residues in the cytoplasmic domain, thereby activating signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, and leading to cell cycle progression, cell differentiation and proliferation.

The degree of malignancy of many epithelial cell cancers is closely related. In recent years, the antibody drugs have achieved breakthroughs in treatment of serious disease such as tumors and autoimmune diseases owing to their high specificity, efficacy and safety, and have become one of the fastest-growing and most promising fields in the global pharmaceutical industry.

Trop2 (trophoblast cell-surface antigen 2) is a glycoprotein that was initially described as a surface marker of trophoblasts but later found by scientists to have increased expression in many solid tumors and decreased expression in normal tissues. Specifically, Trop2 has moderately high expression rates of up to 89%, 88% and 83% in cervical carcinoma, triple negative breast cancer and urothelial carcinoma, respectively, as well as moderately high expression rates in common cancers such as squamous lung carcinoma, endometrial carcinoma, prostate cancer and colorectal cancer. This makes the Trop2-targeting treatment a promising pan-cancer therapy. An antibody drug developed for Trop2 has already been marketed, indicating the increasingly and widely recognized therapeutic potential of the protein.

In addition, vcMMAE has been demonstrated to be safe and effective in ADC molecules.

Poster Download
AACR2022: YH012, a Novel Bispecific Anti-HER2 and TROP2 Antibody-Drug Conjugate, Exhibits Potent Antitumor Efficacy