Transcenta Holding Limited ("Transcenta") (HKEX: 06628), a global clinical stage biopharmaceutical company with fully-integrated capabilities in discovery, research, development and manufacturing of antibody-based therapeutics, announced late-breaking presentation of preclinical study results of novel humanized LIV-1 antibody based ADCs at 2024 San Antonio Breast Cancer Symposium (SABCS). The ADCs (ADC-1 and ADC-2) were engineered using Transcenta's proprietary antibody with site-specifical conjugation of Topoisomerase I Inhibitor payloads and these ADCs demonstrated significantly higher tumor regression activities than MMAE based ADCs in triple-negative breast cancer (TNBC) tumor models.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, the responses are typically short lived. Thus, there is an urgent need to develop more effective treatments [1].

LIV-1, a member of the zinc transporter family and an estrogen-regulated gene in metastatic breast cancer, is overexpressed in a high prevalence in breast cancer (93%), including both TNBC and hormone receptor positive breast cancer, as well as in melanoma (82%), prostate (72%), ovarian (48%) and uterine (30%) cancer. This makes LIV-1 an attractive cell surface target for developing ADC therapeutics.

To develop next generation LIV-1 targeting ADC, Transcenta generated a proprietary novel humanized anti-LIV-1 mAb, 48D6, which displayed unique epitope form benchmark antibody, high binding affinity, specificity, excellent internalization ability. The conjugation method also eliminated FcR binding which resulted in significantly reduced non-specific FcR mediated binding and clearance, and improved pharmacokinetics profile in mice.

In vitro studies indicated that breast tumor cells, such as MDA-MB-468 and MCF-7, are more sensitive to Topo I inhibitor than MMAE. Consequently, Transcenta developed two Topo I inhibitor-based ADCs (ADC-1 and ADC-2) using glycotransferase mediated site-specific conjugation. Both ADC-1 and ADC-2 have a drug-to-antibody ratio (DAR) of 4 but with two different Topo I inhibitor payloads. A MMAE based ADC (ADC-3) with the same site-specific conjugation and DAR4 was also synthesized as the control.

Although ADC-1 and ADC-2 displayed similar and specific cytotoxic activities against human LIV-1-expressing tumor cells in vitro, as compared to SGN-LIV1A analog (DAR4) or ADC-3, they exhibited much higher maximal tumor cell killing than SGN-LIV1A analog in vivo. In addition, both ADC-1 and ADC-2 demonstrated a strong bystander effect which is important to overcome tumor heterogeneity.

In vivo pharmacology study revealed that ADC-1 or ADC-2 exhibited dose-dependent and more potent anti-tumor activities than the SGN-LIV1A analog or ADC-3 in the human LIV-1 transfected MDA-MB-468, a TNBC tumor model.

At 3 mg/kg the tumor growth inhibition (TGI)% were: ADC-1 92.4%, ADC-2 94.7%, ADC-3 68.5% and SGN-LIV1A analog 57.0% on Day 30. However, the overall response rate (ORR, 50% reduction of tumor volume from baseline) at 3mg/kg for SGN-LIV1A analog or ADC-3 was 0%, while ORRs of ADC-1 and ADC-2 were 40% and 70%, respectively. At 6 mg/kg, on Day 42, ORRs of ADC-1 and ADC-2 were 90% and 100%, respectively, and complete response (CR) rates were 90% and 100% respectively. The body weight of mice didn't change significantly at either 3 or 6 mg/kg for ADC-1 or ADC-2.

"The significantly enhanced anti-tumor activities of ADC-1 and ADC-2 are likely due to the high affinity binding of 48D6 to LIV-1 and the high cytotoxicity of Topo I inhibitor for breast tumor cells." said Dr. Xueming Qian, Chairman of the Board and CEO at Transcenta, "These data warrant further investigation of the lead LIV-1 targeting ADCs (ADC-1 and ADC-2) as potential next-generation therapeutic agent in LIV-1 positive breast cancer and other solid tumors."

The 47th San Antonio Breast Cancer Symposium (SABCS) held from December 10 to 13, 2024, in San Antonio, Texas, USA. This Symposium is designed to provide state-of-the-art information on the experimental biology, etiology, prevention, diagnosis, and therapy of breast cancer and premalignant breast disease to an international audience of academic and private physicians and researchers.

Reference:

[1] https://www.nature.com/articles/s41586-024-08031-6     

About Transcenta

Transcenta (HKEX: 06628) is a clinical stage biopharmaceutical company with fully integrated capabilities in antibody-based biotherapeutics discovery, research, development and manufacturing.

Transcenta has established global footprint, with Headquarters and Discovery, Clinical and Translational Research Center in Suzhou, Process and Product Development Center and Manufacturing Facility in Hangzhou, and Clinical Development Centers in Princeton, US and in Beijing, Shanghai and Guangzhou of China, and External Partnering Center in Boston and Los Angeles, US. Transcenta is developing 14 therapeutic antibody molecules for oncology and selected non-oncology indications including bone and kidney disorders.

Source: Transcenta Holding Limited