Melflufen is the first Peptide Drug Conjugate (PDC) 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.
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.
Mechanism of action
Melphalan flufenamide, also known as melflufen, is a first-in-class peptide-drug conjugate (PDC) in multiple myeloma that brings cytotoxicity into the tumour cells.
Melflufen enters cells freely due to its lipophilicity, without the need for transporter proteins. Melflufen is rapidly hydrolyzed by peptidases and esterases, which are overexpressed in tumor cells. The hydrolysis creates a concentration gradient that drives further influx of melflufen into the cell, resulting in intracellular accumulation of alkylating agents. This leads to rapid and irreversible nuclear and mitochondrial DNA damage and induction of apoptosis.
1. Rapid Cellular Entry
Melflufen enters cells freely due to its lipophilicity, without the need of transporter proteins.
2. Enzyme Overexpression in Tumor Cells
Peptidases and esterases are enzymes overexpressed in tumor cells and important in protein homeostasis.
3. Enzymatic Hydrolysis and Payload Release
Melflufen is a PDC that utilizes the overexpression of peptidases inside tumor cells and is rapidly hydrolyzed to release cytotoxic hydrophilic alkylating agents.
4. Intracellular Accumulation of Alkylators
The rapid hydrolysis of melflufen creates a concentration gradient that drives further influx of melflufen into the cell, resulting in intracellular peak of alkylating agents.
5. Irreversible DNA Damage
Alkylating metabolites of melflufen cause irreversible nuclear and mitochondrial damage by linking DNA strands which induces apoptosis.
6. Activity in Resistant Myeloma Cells
Melflufen is able to overcome p53 (TP53)-deficiency-mediated resistance seen in conventional alkylators.
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Our focus
Multiple myeloma
Multiple myeloma is an incurable blood cancer. Symptoms like bone pain, fatigue, and infections severely reduce quality of life. Despite advances in treatment, most patients eventually relapse and become resistant to all available therapies, creating a critical need for innovative options.