Enhanced CDC of B cell chronic lymphocytic leukemia cells mediated by rituximab combined with a novel anti-complement factor H antibody

• Published in: PloS one 2017-06, Vol.12 (6), p.e0179841-e0179841
• Main Authors: Winkler, Mark T, Bushey, Ryan T, Gottlin, Elizabeth B, Campa, Michael J, Guadalupe, Eross S, Volkheimer, Alicia D, Weinberg, J Brice, Patz, Jr, Edward F
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Analysis; Antibodies - immunology; Antibodies - therapeutic use; Antineoplastic Agents - therapeutic use; B cells; Biology and Life Sciences; Cancer therapies; CD59 antigen; Chronic lymphocytic leukemia; Complement; Complement Activation - drug effects; Complement Activation - immunology; Complement factor H; Complement Factor H - immunology; Complement regulatory proteins; Cytotoxicity; Dosage and administration; Drug therapy; Female; Flow Cytometry; Hematology; Humans; Immunoglobulins; Immunology; Immunotherapy; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Lymphatic leukemia; Lymphocyte receptors; Lymphocytes B; Lymphocytic leukemia; Male; Medicine and Health Sciences; Membrane proteins; Middle Aged; Monoclonal antibodies; Mutation; Neutralizing; Patients; Proteins; Research and Analysis Methods; Resistance factors; Rituximab; Rituximab - therapeutic use; Targeted cancer therapy; Therapy; Toxicity; Treatment outcome
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0179841

Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL) has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC) due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH). We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL.