Novel indications of mannan-binding lectin (MBL) in the treatment of immunocompromised individuals

#The present invention pertains to the use of subunits and oligomers of mannan-binding lectin (MBL) in prophylactic and/or curative treatment of an immunocompromised individual.

#Several groups of lectins, i.e., carbohydrate-binding proteins, are known in man. One group is the C-type lectins. The C-type lectins contain a calcium-dependent carbohydrate recognition domain (a C-type CRD)1. Mannan-binding lectin (MBL), synonymous to mannose-binding lectin, mannan-binding protein or mannose-binding protein (MBP), belongs to the subgroup of C-type lectins, termed collectins, since these soluble proteins are composed of subunits presenting three CRDs attached to a collagenous stalk2. MBL interact with carbohydrates presented by a wide range of micro-organisms and accumulating evidence shows that it plays an important role in the innate immune defence3. When bound to carbohydrate MBL is able to activate the complement system.

#The complement system may be activated via three different pathways: the classical pathway, the alternative pathway, and the newly described third pathway, the mannan-binding lectin (MBL) pathway which is initiated by the binding of MBL to carbohydrates presented by micro-organisms. The components of the alternative pathway and of the MBL pathway are parts of the innate immune defence, also termed the natural or the non-clonal, immune defence, while the classical pathway involves cooperation with antibodies of the specific immune defence4.

#FIG. 1: The distribution of MBL concentrations in the plasma of in leukemia patients divided into patients with clinically significant infections (CSI) and non-CSI patients.

#FIG. 2: The distribution of MBL concentrations in the plasma of multiple myeloma patients divided into those with clinically significant infections (CSI) and non-CSI patients.

#The following example demonstrates the results of an examination of the influence of MBL deficiency on the occurrence of clinically significant infections in a group of hematologic individuals undergoing chemotherapy.

#Study Population

#The study encompasses examination of a consecutive series of patients attending Department of Haematology, Aarhus University, Denmark. The majority of these patients received chemotherapy. They included 7 with acute myeloid leukaemia, 17 with multiple myeloma (MM), 11 with polycytemia, 13 with Non-Hodgkin's lymphoma, 1 with Burkitt's lymphoma, 1 with Waldenström's macroglobulinemia, 5 with chronic lymphocytic leukaemia, 3 with monoclonal gammapathy of undetermined significance (MGUS), 5 with Hodgkin's lymphoma, 2 with chronic myeloid leukaemia, 1 with acute lymphoid leukaemia, 1 with aplastic anaemia and 1 with myelofibrosis. With regard to the MM group they all received chemotherapy. Three different treatments were used; VAD: vincristine (0.4 mg per 24 hours) and doxorubicin (Adriamycin) (9 mg per m2 per 24 hours) given by continuous infusion for 4 days and dexamethasone (40 mg, p.o.) for 4 days on days 1 through 4, 9 through 12 and 17 through 20 of each 28 day cycle; NOP: mitoxantron (10 mg per m2) and vincristine (1,4 mg per m2) given by continuous infusion one time and prednisone (2×50 mg, p.o.) every day of each cycle; MP: melphalan (0.25 mg/kg/day) by infusion for 4 days and prednisone (2×50 mg, p.o.) for 4 days.