Melflufen – first PDC with an alkylating payload
Melflufen is the first Peptide Drug Conjugate (PCD) with an alkylating payload. The drug utilizes peptidases and esterases that are overexpressed in multiple myeloma cells, to release a toxic payload inside cells, to damage DNA and kill cancer cells.
Mechanism of action
Melflufen is rapidly taken up by myeloma cells due to its lipophilicity. The drug is hydrolyzed by enzymes called peptidases and esterases to release a hydrophilic cytotoxic payload that becomes entrapped in the cells. These enzymes are upregulated in cancer cells and play a key role in protein homeostasis, cell-cycle progression and programmed cell death. Increased aminopeptidase expression is associated with advanced disease and a worse utcome in multiple myeloma.
Read more about the Mechanism of action
The melflufen molecule
In vitro, melflufen is 50-fold more potent in myeloma cells than the toxic payload melphalan itself, due to increased concentration of the toxic payload in the cells. Melflufen has cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators. It inhibits angiogenesis and metastatic processes in preclinical studies and overcomes p53-deficiency-mediated resistance, a common mechanism of resistance to antimyeloma therapies. Melflufen rapidly induces irreversible DNA damage leading to apoptosis of myeloma cells.
