A first patient has been dosed in a Phase I Clinical trial of BRY812, a third-generation antibody-drug conjugate (ADC) targeting LIV-1 being developed by BioRay Pharmaceutical Co., for the treatment of advanced malignant tumors.
The leading institution of this clinical trial is Sun Yat-sen Memorial Hospital of Sun Yat-sen University, and the principal investigators are academician Song Erwei and Professor Yao Herui.
Novel targets
To date more than 12 ADCs have been developed for the treatment of various forms of cancers and hematological malignancies. For example, in the treatment of breast cancer, these ADCs include trastuzumab emtansine (Kadcyla®; Roche/Genentech), trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca) and sacituzumab govitecan (Trodelvy®; Gilead), primarily targeting HER2 and TROP-2.
However, in addition to these ADCs, promising new ADCs with novel targets are currently under investigation and (early) development with encouraging results. These targets include, but are not limited to, HER3, LIV-1, ROR1-2, and B7-H4.
Targeting LIV-1
LIV-1, also known as SLC39A6 or ZIP6, is a multipass transmembrane protein belonging to the ZIP superfamily of zinc transporters, possesses zinc transporter and metalloproteinase activities. LIV-1 directly participates in the homeostasis metabolism of intracellular zinc ions, facilitating the transport of zinc ions from the extracellular space or intracellular organelles to the cytoplasm, influencing cell growth.
LIV-1 was first described in 1988 as an estrogen regulated gene with later work suggesting a role for this transporter in cancer growth and metastasis.[1]
Zinc is very common in biological processes. Hence, researchers believe that aberrations in zinc status may play a significant role in cellular dysfunction, including the development and/or progression of cancer. Zinc is known to play an important role in cell proliferation, [2][3] and tumor growth. [4][5][6]
BRY812
BRY812 uses BioRay Pharmaceutical’s proprietary CysLink™ irreversible chemical conjugation technology platform and highly stable linker to conjugate the antibody with the toxin. By binding to LIV-1 on the surface of tumor cells, the ADC-target complex enters the tumor cell’s lysosome through endocytosis, releasing small molecule toxins that selectively kill tumor cells. BRY812 has shown significant tumor growth inhibition in preclinical studies, and demonstrated excellent anti-tumor activity that is potentially superior to similar drugs.
Compared to other drugs of the same class, it exhibits higher circulation stability, effective release of the payload within the tumor while significantly reducing toxin shedding and exchange in serum. This provides BRY812 with a great safety profile and an improved therapeutic window. Furthermore, BRY812 can also induce immunogenic cell death (ICD) and enhance the anti-tumor effects of immunotherapies such as anti-PD-(L)1.
“The significant market potential of ADCs requires differentiation in the market competition and expanding coverage to a broader patient population,” noted Zhu Wei, MD, Chief Medical Officer of BioRay.
“As the first Chinese (domestic) ADC targeting LIV-1 to enter clinical trials, BRY812 is expected to treat various advanced malignant tumors, meet more clinical medication needs, and provide more treatment options for patients,” Wei concluded.
To date, there are no approved drugs worldwide that target LIV-1, making BioRay’s BRY812 the first LIV-1 ADC in China and the second to enter clinical trials globally.
ADC Drug Map
Description of BRY812
Highlights of prescribing information
Trastuzumab emtansine (Kadcyla®; Roche/Genentech)[Prescription information]
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Sacituzumab govitecan (Trodelvy®; Gilead)[Prescribing Information]
Reference
[1] Grattan BJ, Freake HC. Zinc and cancer: implications for LIV-1 in breast cancer. Nutrients. 2012 Jul;4(7):648-75. doi: 10.3390/nu4070648. Epub 2012 Jul 4. PMID: 22852056; PMCID: PMC3407987.
[2] Prasad AS, Beck FW, Endre L, Handschu W, Kukuruga M, Kumar G. Zinc deficiency affects cell cycle and deoxythymidine kinase gene expression in HUT-78 cells. J Lab Clin Med. 1996 Jul;128(1):51-60. doi: 10.1016/s0022-2143(96)90113-4. PMID: 8759936.
[3] Paski SC, Xu Z. Growth factor stimulated cell proliferation is accompanied by an elevated labile intracellular pool of zinc in 3T3 cells. Can J Physiol Pharmacol. 2002 Aug;80(8):790-5. doi: 10.1139/y02-101. PMID: 12269789.
[4] DeWys W, Pories W. Inhibition of a spectrum of animal tumors by dietary zinc deficiency. J Natl Cancer Inst. 1972 Feb;48(2):375-81. PMID: 4652380.
[5] Takeda A, Goto K, Okada S. Zinc depletion suppresses tumor growth in mice. Biol Trace Elem Res. 1997 Winter;59(1-3):23-9. doi: 10.1007/BF02783226. PMID: 9522043.
[6] McQuitty JT Jr, DeWys WD, Monaco L, Strain WH, Rob CG, Apgar J, Pories WJ. Inhibition of tumor growth by dietary zinc deficiency. Cancer Res. 1970 May;30(5):1387-90. PMID: 5448539.
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