Melflufen - a peptidase-potentiated alkylating agent in clinical trials

Abstract

Aminopeptidases like aminopeptidase N (APN, also known as CD13) play an important role not only in normal cellular functioning but also in the development of cancer, including processes like tumor cell invasion, differentiation, proliferation, apoptosis, motility, and angiogenesis. An increased expression of APN has been described in several types of human malignancies, especially those characterized by fast-growing and aggressive phenotypes, suggesting APN as a potential therapeutic target.Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated alkylating agent. Melflufen readily penetrates membranes and an equilibrium is rapidly achieved, followed by enzymatic cleavage in aminopeptidase positive cells, which results in trapping of less lipophilic metabolites. This targeting effect results in very high intracellular concentrations of its metabolite melphalan and subsequent apoptotic cell death. This results in a potency increase (melflufen vs melphalan) ranging from 10- to several 100-fold in different in vitro models. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. Furthermore, anti-angiogenic properties of melflufen have been described.Consequently, it is hypothesized that melflufen could provide better efficacy but no more toxicity than what is achieved with melphalan, an assumption so far supported by experiences from hollow fiber and xenograft studies in rodents as well as by clinical data from patients with solid tumors and multiple myeloma. This review summarizes the current preclinical and clinical knowledge of melflufen.

Melflufen, a peptide‐conjugated alkylator, is an efficient anti‐neo‐plastic drug in breast cancer cell lines

“…We also demonstrated that knock down of CD13 in D492HER2 cells reduced the efficacy of melflufen further demonstrating the importance of CD13 for the activity of melflufen in D492HER2 cells. The efficient activity of melflufen in cancer cells has been documented in several articles (reviewed in 21 ). Chauhan et al demonstrated that melflufen was highly efficient in killing myeloma cells, even cells that had acquired resistance to melphalan.…”

Melflufen: A Peptide–Drug Conjugate for the Treatment of Multiple Myeloma

“…Melflufen is a PDC that is being investigated in multiple myeloma and other hematologic malignancies, immunoglobulin light chain (AL) amyloidosis, and solid tumors [ 29 , 33 , 34 ].…”

“…Melflufen is highly lipophilic, which promotes its rapid uptake by cells [ 29 , 30 , 31 , 35 ] ( Figure 1 ). Once within the cell, melflufen releases its hydrophilic alkylator payloads via the hydrolytic activity of intracellular peptidases (e.g., aminopeptidases) [ 30 ].…”

“…Melphalan flufenamide (melflufen) is a first-in-class peptide–drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells [ 28 , 29 , 30 , 31 , 32 ]. Because of its distinct mechanism of action, melflufen is well suited for use in third-line therapy both in patients who have not received prior alkylator therapy, such as older patients and those who are not eligible for transplant, as well as in patients who have prior exposure to melphalan [ 29 ]. This review describes the historical development of melflufen, its mechanism of action, and the ongoing clinical development program for melflufen in multiple myeloma.…”

Updates and rationale of clinical trials in multiple myeloma

“…Melflufen is newer generation alkylator therapy and a modified derivative of one of the oldest MM therapies, melphalan. Melflufen is activated by aminopeptidases and its metabolites are more lipophilic than melphalan, allowing better transport across cell membranes . Recent phase II data from the HORIZON Trial of melflufen plus dexamethasone in RRMM reported 33% overall response rate (ORR) and 4 months PFS among 82 evaluable patients.…”