Melflufen - a peptidase-potentiated alkylating agent in clinical trials

Malin Wickström _, Peter Nygren, Rolf Larsson, Johan Harmenberg, Jakob Lindberg, Per Sjöberg, Markus Jerling, Fredrik Lehmann, Paul Richardson, Kenneth Anderson, Dharminder Chauhan and Joachim Gullbo

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Oncotarget. 2017; 8:66641-66655. https://doi.org/10.18632/oncotarget.18420

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Malin Wickström1,2, Peter Nygren1,3, Rolf Larsson1, Johan Harmenberg4, Jakob Lindberg4, Per Sjöberg4, Markus Jerling4, Fredrik Lehmann5, Paul Richardson6, Kenneth Anderson6, Dharminder Chauhan6 and Joachim Gullbo1,3

1 Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, Uppsala SE, Sweden

2 Department of Women’s and Children’s Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden

3 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

4 Oncopeptides AB, Stockholm, Sweden

5 Recipharm OT Chemistry AB, Uppsala, Sweden

6 Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

Correspondence to:

Joachim Gullbo, email:

Keywords: melflufen, aminopeptidase, cancer, targeted chemotherapy

Received: October 09, 2016 Accepted: April 17, 2017 Published: June 08, 2017


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.

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