YH012 is a bispecific antibody-drug conjugate (ADC) developed using Biocytogen’s RenLite platform, which targets HER2 and TROP2 and is intended for the treatment of solid tumors. YH012 utilizes fully human antibodies with a common light chain, which simplifies purification and drug conjugation. The ADC structure enables specific identification of tumor cells and induction of drug endocytosis, leading to tumor cell killing. The conjugated drug is vcMMAE with a DAR value of 4. YH012 is currently in the CMC stage.
Preclinical studies have demonstrated the following findings:
1. YH012 specifically targets tumor cells with HER2 and TROP2 co-expression, which minimizes the risk of attacking normal tissue cells, thus reducing potential side effects and improving safety. Additionally, the two targets result in a synergistic effect, enhancing the therapeutic potential of YH012.
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
3. Anti-HER2 x TROP2 BsAb exhibits greater endocytosis than the parental monoclonal antibodies.
4. YH012 has a simple structure and good stability, which greatly improves the CMC efficiency. Light chain mismatches can be prevented by using RenLite mice; and heavy chains are assembled with the knob-into-hole (KIH) technology.
HER2, also known as ErbB2, is a transmembrane protein that belongs to the human epidermal growth factor receptor (EGFR) family. It lacks a known ligand-binding domain but is capable of forming heterodimers with other members of the EGFR family, including EGFR, HER3 (ErbB3), and HER4 (ErbB4), which can activate downstream signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways.
HER2 is frequently overexpressed in many types of cancer, including breast, ovarian, gastric, and lung cancer, and is associated with a poor prognosis. HER2 overexpression can lead to constitutive activation of signaling pathways, resulting in increased cell proliferation, survival, and migration, as well as resistance to chemotherapy and radiation therapy. Targeted therapies, such as trastuzumab and pertuzumab, have been developed to specifically inhibit HER2 activity and have demonstrated clinical benefits in patients with HER2-positive breast cancer.
Trop2 (trophoblast cell-surface antigen 2) is a glycoprotein initially identified as a surface marker of trophoblasts. Later, researchers found that it is overexpressed in many solid tumors while having low expression in normal tissues. Specifically, Trop2 has moderate to high expression rates of up to 89%, 88%, and 83% in cervical carcinoma, triple negative breast cancer, and urothelial carcinoma, respectively, as well as moderate expression rates in other common cancers such as squamous lung carcinoma, endometrial carcinoma, prostate cancer, and colorectal cancer. As a result, Trop2-targeting treatment is a promising pan-cancer therapy. An antibody drug developed for Trop2 has already been marketed, demonstrating the therapeutic potential of the protein and its increasing recognition by the scientific community.
AACR 2023: A First-In-Class Anti-HER2/TROP2 Bispecific Antibody-Drug Conjugate (YH012) Exhibits Potent Anti-Tumor Efficacy
AACR 2022: YH012, a Novel Bispecific Anti-HER2 and TROP2 Antibody-Drug Conjugate, Exhibits Potent Antitumor Efficacy