Abstract B075: Anti-human LIV-1 antibody drug conjugate for treatment of metastatic prostate cancer

Abstract In the worldwide male population, prostate cancer has the most frequent malignancy; out of all the cancer-related causes of deaths, it is also one of the most common. With the advance of new therapies of androgen receptor pathway inhibitors, patient survival rates have improved significantly. There are still tremendous unmet needs, however, for the patients with treat-refractory metastatic castration-resistant prostate cancer (mCRPC). LIV-1, also known as SLC39A6 or ZIP6, is a member of the zinc transporter family and was first identified as an estrogen-inducible gene in breast cancer. Previous studies with immunohistochemical (IHC) analysis showed that LIV-1 is expressed by estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites) and ER-/PR-/Her2- (triple-negative) breast cancers. These studies also showed that in healthy human tissues, LIV-1 expression is limited to hormonally-regulated organs (prostate, uterus, and breast). The broad expression of LIV-1 in prostate and breast cancer tumors in combination with the limited expression in vital organs makes LIV-1 an excellent target for an antibody-drug conjugate (ADC). We generated an ADC, BRY812, consisting of a humanized anti-LIV-1 mAb conjugated to monomethyl auristatin E (MMAE), via a novel conjugation method that prevents MMAE from coming off of the antibody during the circulation. The PK studies in rat and monkey showed that the free MMAE released from ADC is 1 to 2 log lower compared with approved ADCs prepared by the standard conjugation method. Low free MMAE concentration significantly lowers the risk of off target toxicity by the ADC. In vitro and in vivo studies demonstrated the antitumor activity of BRY812 for the treatment of prostate and ER+ and triple-negative breast cancers with a better safety profile and a larger therapeutic window. The humanized LIV-1 ADC, BRY812 is currently in preclinical toxicity studies and will advance to First-in-Human trials in April, 2023. Citation Format: Xiaobei Zhao, Gang Chen. Anti-human LIV-1 antibody drug conjugate for treatment of metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B075.