Glycolipid containing compositions for use in the treatment of tumors

#The invention relates to pharmaceutical compositions comprising the α-Gal glycolipid (9Z,9′Z)-(2R)-3-(((2-(6-((3-(((2R,3R,4R,5S,6R)-3-acetamido-5-(((2S,3R,4S,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)propyl)amino)-6-oxohexanamido)ethoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl bis(octadec-9-enoate) (α-Gal BOEL) for use in treating tumours. The invention also relates to methods of treating tumours using said compositions.

#The major cause of death in cancer patients with solid tumours is the recurrence of the cancer after surgery as multiple metastases are non-resectable and/or refractory to any therapy. The majority of these patients are considered to have a terminal cancer disease. As no treatment is available for them, many of these patients die within weeks or a few months after detection of metastatic tumour lesions.

#Tumours develop in cancer patients because the immune system fails to detect tumour cells as cells that ought to be destroyed. Tumour cells express autologous tumour antigens in a large proportion of cancer patients. These autologous tumour antigens may elicit a protective anti-tumour immune response. Tumour cells, or tumour cell membranes, have to be internalized by antigen presenting cells in order to induce the development of an anti-tumour immune response. However, the immune system in cancer patients displays “ignorance” toward the tumour antigens that is associated with early development of the tumour in a “stealthy” way, so it is “invisible” to antigen presenting cells (Pardoll D M. Clin. Immunol. 2000; 95:S44-49; and Dunn G P et al. Nat Immunol 2002; 3: 991-8).

#FIG. 1: The structure of α-Gal BOEL.

#FIG. 2: Data to demonstrate that α-Gal BOEL binds to anti-Gal antibodies.

#FIG. 3: Data to demonstrate that α-Gal BOEL induces complement mediated cell lysis of cancer cells.

#The invention described herein provides a composition and method that enables α-Gal glycolipids (i.e. α-Gal BOEL) to be inserted into the cell membrane of tumour cells within a treated tumour. It is believed that the presence of α-Gal glycolipids in the tumour lesion results in the destruction or regression of the tumour by the immune mediated inflammatory process that is induced by the interaction between the natural anti-Gal antibodies present in the subject and the α-Gal epitope of α-Gal BOEL. Moreover, this treatment converts the treated tumour into a vaccine that elicits a systemic protective anti-tumour immune response that prevents the development of distant metastases by immune destruction of metastatic tumour cells.

#The invention described herein comprises a therapy treatment modality that includes, but is not limited to, intratumoural delivery of a specific glycolipid, referred to as α-Gal BOEL, that carries the α-Gal epitope and therefore may be referred to as an “α-Gal glycolipid”. The α-Gal glycolipid inserts into the outer leaflet of the cell membrane of tumour cells within the treated lesion. The presence of α-Gal glycolipids in the tumour lesion achieves two goals: 1. Immune mediated destruction of tumour lesions by the inflammatory process that is induced within the tumour lesion by the interaction between the natural anti-Gal antibody and the α-Gal epitopes of α-Gal glycolipids inserted in tumour cell membranes; and 2. Effective uptake by antigen presenting cells of tumour cells and tumour cell membranes with inserted α-Gal glycolipids and thus, expressing α-Gal epitopes that bind in situ anti-Gal antibodies, thereby converting the treated tumour lesion into an autologous tumour vaccine.

#Although it is not necessary to understand the mechanism of an invention, it is believed that this uptake results in an effective immune response against tumour antigens present on or within the tumour cells expressing α-Gal epitopes. It is further believed that this immune response may result in immune mediated destruction of metastatic tumour cells that do not express α-Gal epitopes, but express the tumour antigen.