Ofatumumab (OFA), a human CD20-targeting mAb, kills B lymphocytes using the innate immune system including complement-dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples col...

Neuromyelitis optica spectrum disorders (herein called NMO) is an inflammatory demyelinating disease of the central nervous system in which pathogenesis involves complement-dependent cytotoxicity (CDC) produced by immunoglobulin G autoantibodies targeting aquaporin-4 (AQP4-IgG) on astrocytes. We reported evidence previously, using CD59-/- mice, that the membrane-associated complement inhibitor ...

A light and electron microscopic study of antibody-dependent lymphocytotoxicity was carried out with the object of elucidating the mechanisms responsible for the cell killing, the basis for the research being the relationship that has recently been shown to exist between the morphology of cell death and its pathogenesis. Chang liver cells coated with a rabbit anti-human antibody were used as ta...

This paper includes a review of the relative importance of pretransplant complement-fixing and non-complementing-fixing human leukocyte antigen (HLA) and non-HLA antibodies (Abs). Sera from 565 adult cardiac transplant recipients were retrospectively analysed for the presence of HLA antibodies using complement-dependent cytotoxicity (CDC), HLA-coated Luminex beads, and C4d deposition on Luminex...

Local acidosis is a common feature of allergic, vascular, autoimmune, and cancer diseases. However, few studies have addressed the effect of extracellular pH on the immune response. Here, we analyzed whether low pH could modulate complement-dependent cytotoxicity (CDC) against IgG-coated cells. Using human serum as a complement source, we found that extracellular pH values of 5.5 and 6.0 strong...

IgG antibodies can organize into ordered hexamers on cell surfaces after binding their antigen. These hexamers bind the first component of complement C1 inducing complement-dependent target cell killing. Here, we translated this natural concept into a novel technology platform (HexaBody technology) for therapeutic antibody potentiation. We identified mutations that enhanced hexamer formation an...

The CD20 mAbs, rituximab (RTX) and ofatumumab (OFA), have been used with success in the clinic in the treatment of B cell malignancies. These mAbs can eliminate B cells only by utilizing the body’s immune effector mechanisms, and there is considerable evidence that OFA is particularly effective at eliminating B cells by mediating complement dependent cytotoxicity (CDC). However, effector mechan...

We examined complement-dependent cytotoxicity (CDC) by hexamer formation-enhanced CD20 mAb Hx-7D8 of patient-derived chronic lymphocytic leukemia (CLL) cells that are relatively resistant to CDC. CDC was analyzed in normal human serum (NHS) and serum from an individual genetically deficient for C9. Hx-7D8 was able to kill up to 80% of CLL cells in complete absence of C9. We conclude that the na...

BACKGROUND Autoreactive B cells are crucial players in the pathogenesis of rheumatoid arthritis (RA). Autoantibodies specific for citrullinated proteins (ACPA), present in the serum of approximately 60-70 % of patients, have a pathogenic role in the disease. B cell depleting therapies may result in a transient immunosuppression, increasing the risk of infections. Our aim was to develop a new th...

Rituximab efficacy in cancer therapy depends in part on induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex, thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell non-Hodgkin's lymphoma (NHL), and upregulation of hCD59 is an important determinant of the sens...