Antibodies against Complement Factor H Selectively Destroy Tumor Cells

By LabMedica International staff writers
Posted on 17 May 2016

Cancer researchers have identified and produced a monoclonal antibody that destroys tumor cells by blocking the activity of the protective protein complement factor H (CFH).

Investigators at Duke University (Durham, NC, USA) had reported previously an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. Patients with stage I NSCLC (non-small cell lung cancer) had a significantly higher incidence of anti-CFH antibody than those with late-stage NSCLC. This association led to the hypothesis that CFH antibodies that arise in lung cancer patients may promote anti-tumor cell activity and that CFH antibody administration might provide a unique way to stimulate a long-term immune response and treat cancer.

Image: Molecular structure of factor H bound to C3b. In order to avoid self-attack, regulatory proteins such as factor H bind with C3b, a central component of the enzyme C3 convertase, to help the immune system recognize the body’s own tissue and keep complement in check (Photo courtesy of the University of Pennsylvania School of Medicine).

CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. CHF is a member of the regulators of complement activation family and is a complement control protein. It is a large (155 kilodaltons), soluble glycoprotein that circulates in human plasma (at typical concentrations of 200–300 micrograms per milliliter). Its principal function is to regulate the Alternative Pathway of the complement system, ensuring that the complement system is directed towards pathogens or other dangerous material and does not damage host tissue.

In the current study the investigators isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B-cells obtained from patients with the antibody.

They reported in the May 5, 2016, online edition of the journal Cell Reports that the co-crystal structure of a CFH antibody-target complex showed a conformational change in the target relative to the native structure. This recombinant CFH antibody caused complement activation and release of anaphylatoxins, killed tumor cells in vitro, and inhibited tumor growth in vivo.

"This is the first completely human-derived antibody developed as an anti-cancer therapy, which is very different from other immunotherapy approaches," said senior author Dr. Edward F. Patz, Jr., professor of pharmacology and cancer biology at Duke University. "This could represent a whole new approach to treating cancer, and it is exciting because the antibody selectively kills tumor cells, so we do not have significant side effects to achieve tumor control. We believe we can modulate the immune response and let the body's own immune system take over to either kill the tumor or keep it from growing."

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Duke University