ALT-P7

The main marine-derived drugs that have been studied for the treatment of BC are tubulin-binding agents (eribulin and plocabulin), DNA-targeting agents (cytarabine and minor groove binders-trabectedin and lurbinectedin) and Antibody-Drug Conjugates (ADCs)...Among these, clinical data are available on ladiratuzumab vedotin and glembatumumab vedotin in TNBC, and on disitamab vedotin and ALT-P7 in HER2-positive patients. A deeper knowledge of the mechanism of action and of the potential predictive factors for response to marine-derived drugs is important for their rational and effective use, alone or in combination. In this narrative review, we discuss the role of marine-derived drugs for the treatment of BC, although most of them are not approved, and the opportunities that could arise from the potential treasure trove of the sea for novel BC therapeutics.

A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.

Background: ALT-P7 is an antibody-drug conjugate, in which two molecules of monomethyl auristatin E (MMAE) are site-specifically conjugated to a cysteine-containing peptide motif of trastuzumab variant... ALT-P7 was well tolerated to a dose of 4.2mg/kg in heavily pretreated HER2-positive advanced breast cancer. DLTs were observed at 4.8mg/kg, and 4.5mg/kg is under evaluation. The observed clinical activity warrants further evaluation in a phase 2 trial.