The immunomodulator mifamurtide (liposomal muramyltripeptide phosphatidyl ethanolamine [L-MTP-PE]) is a synthetic lipophilic acylate dipeptide analogue sold by IDM pharmaceutical as a treatment for osteosarcoma. Mifamurtide can activate macrophages and monocytes to release chemicals with potential tumoricidal effects, help to control microscopic metastatic disease, which has been safely given together with standard adjuvant chemotherapy to patients with high-grade osteosarcoma.
Studies have found that the response of factors released by the host immune system, such as macrophages, to either neomycin or bacterial products can promote tumor necrosis. The release of macrophages requires detection of the molecular properties of pathogens, such as the nucleotide binding and oligomerization domain-2 (NOD2). The intracellular pattern-recognition molecule NOD2 detects the pattern of muramyl dipeptide (MDP). Mifamurtide (L-MTP-PE) is a fully synthetic lipophilic derivate of MDP, and therefore, it is most likely also a ligand and an activator of NOD2 and other targets of MDP. NOD2 from a tissue-specific expression pattern, and its expression is mainly restricted to monocytes, macrophages, Dentritic cells, and intestinal Paneth cells.
Mifamurtide is used in combination with postoperative, multiagent chemotherapy to kill remaining cancer cells and improve a patient's chance of overall survival. In a clinical trial about 800 newly diagnosed osteosarcoma patients, mifamurtide was combined with the chemotherapeutic agents doxorubicin and methotrexate. The mortality could be lowered by 30% versus chemotherapy plus placebo. Six years after the treatment, 78% of patients were still alive. It is noteworthy that proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor- α (TNF-α), have different roles in cancer, which can be associated with fatigue, depression, cognitive impairment, cachexia, anorexia, and pain (all of which negatively affect the quality of life). They can influence the metabolism of certain anticancer drugs by acting on cytochrome P450 enzymes that enables the survival of certain cancer cells and they might become resistant to chemotherapy and radiotherapy. Clinical investigations, however, suggest that mifamurtide may result in a net positive effect in patients treated for osteosarcoma.
Pharmacokinetics and metabolism
Mifamurtide is a form of MDP, which promotes the production of inflammatory cytokines through the recognition of macrophages, thus promoting the effect of sterilization and tumor killing. The researchers evaluated the subcutaneous injection, which cleared mifamurtide rapidly from plasma in cancer patients and healthy adults, and the liposomes are mainly phagocytosed by the cells of the reticuloendothelial system (RES). In a biodistribution investigation in patients with osteosarcoma, mTc-labeled L-MTP-PE was found 6 hours after infusion in liver, spleen, nasopharynx, thyroid, and, to a lesser extent, in the lung, and this distribution pattern is consistent with that of the RES. There is no evidence of accumulation of L-MTP-PE or free MTP-PE.
1. Leo Kager, Ulrike Pötschger, Stefan Bielack. Review of mifamurtide in the treatment of patients with osteosarcoma. Therapeutics and Clinical Risk Management, 2010:6 279–286.
2. Meyers, Paul A. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. EXPERT REVIEW OF ANTICANCER THERAPY, 2009,9(8),1035-1049.