According to the Zhito Finance APP, TRANSCENTA-B (06628) announced the latest preclinical research results of a novel antibody-drug conjugate (ADC) based on humanized LIV-1 antibodies at the 2024 San Antonio Breast Cancer Symposium (SABCS). The two antibody-drug conjugates, ADC-1 and ADC-2, utilize the company’s proprietary antibodies designed to specifically bind to topoisomerase I inhibitor payloads. These two antibody-drug conjugates demonstrated tumor regression activity in triple-negative breast cancer (TNBC) models, significantly higher than the MMAE-based ADC.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with the highest recurrence rate. The main standard treatment for advanced triple-negative breast cancer is systemic chemotherapy, with or without immunotherapy; however, the relief brought by these treatments is often short-lived. Therefore, there is an urgent need for the development of more effective therapies.

LIV-1 is a member of the zinc transporter family and an estrogen-regulated gene in metastatic breast cancer. It is highly expressed in breast cancer (93%), including TNBC and hormone receptor-positive breast cancer, as well as in melanoma (82%), prostate cancer (72%), ovarian cancer (48%), and uterine cancer (30%). This makes LIV-1 a noteworthy cell surface target for the development of ADC therapies.

To develop the next generation of LIV-1 ADC, the company has developed 48D6, a proprietary novel humanized anti-LIV-1 monoclonal antibody. This antibody has a unique binding epitope, high binding affinity, specificity, and excellent internalization capacity. The conjugation method also eliminates FcR binding, significantly reducing non-specific FcR-mediated binding and clearance while improving pharmacokinetic properties in mice.

In vitro studies indicate that breast tumor cells, such as MDA-MB-468 and MCF-7, show higher sensitivity to topoisomerase I inhibitors compared to MMAE. Therefore, the company has adopted glycosyltransferase-mediated specific site conjugation to develop two antibody-drug conjugates (ADC-1 and ADC-2) based on topoisomerase I inhibitors. Both ADC-1 and ADC-2 have a drug-antibody ratio (DAR) of 4 but utilize two different topoisomerase I inhibitor payloads. As a control, an MMAE-based antibody-drug conjugate (ADC-3) with the same specific site conjugation and drug-antibody ratio was also synthesized.

Although ADC-1 and ADC-2 exhibited similar and specific cytotoxic activity in vitro against human LIV-1 expressing tumor cells as the SGN-LIV1A analog (DAR4) or ADC-3, they demonstrated significantly higher maximum tumor cell killing ability in vivo than the SGN-LIV1A analog. Furthermore, both ADC-1 and ADC-2 exhibited a strong bystander effect, which is critical for overcoming tumor heterogeneity.

The results of in vivo pharmacology studies indicate that ADC-1 and ADC-2 demonstrate dose-dependent and stronger antitumor activity than the SGN-LIV1A analog or ADC-3 in human LIV-1 transfected MDA-MB-468 (a TNBC model).

At a dose of 3 mg/kg on day 30, the tumor growth inhibition rate (TGI) % was as follows: ADC-1 92.4%, ADC-2 94.7%, ADC-3 68.5%, SGN-LIV1A analog 57.0%; however, at a dose of 3 mg/kg, the overall response rate (ORR, defined as a 50% reduction in tumor volume compared to baseline) for the SGN-LIV1A analog or ADC-3 was 0%, while the ORR for ADC-1 and ADC-2 were 40% and 70% respectively. At a dose of 6 mg/kg on day 42, the ORR for ADC-1 and ADC-2 were 90% and 100% respectively, with complete response rates (CR) of 90% and 100%. There was no significant effect on mouse body weight for ADC-1 or ADC-2 at doses of either 3 mg/kg or 6 mg/kg.

"The significantly enhanced antitumor activity of ADC-1 and ADC-2 may be attributed to the high-affinity binding of 48D6 to LIV-1 and the high cytotoxicity of topoisomerase I inhibitors on breast tumor cells," said Dr. Qian Xueming, Chairman and CEO of the company. "These data provide a basis for further research on LIV-1 ADCs (ADC-1 and ADC-2), which hold promise as the next generation of therapeutic agents for LIV-1 positive breast cancer and other solid tumors."