Trifunctional antibody

A trifunctional antibody is a monoclonal antibody with binding sites for two different antigens, typically CD3 and a tumor antigen, making it a type of bispecific monoclonal antibody. In addition, its intact Fc-part can bind to an Fc receptor on accessory cells like conventional monospecific antibodies. The net effect is that this type of drug links T cells (via CD3) and monocytes/macrophages, natural killer cells, dendritic cells or other Fc receptor expressing cells to the tumor cells, leading to their destruction.^[1]

At an equivalent dose a trifunctional antibody is more potent (more than 1,000-fold) in eliminating tumor cells than conventional antibodies.

Trifunctional antibodies were the first type of bispecific monoclonal antibodies to be produced. The first concepts date back to the mid-1980s.[12]^[13] For over twenty years, no such antibody was approved for clinical use, mainly because of manufacturing difficulties. Immunogenicity results from the fact that appropriate parental antibodies are obtained from rat and mice. After application, the patient's immune system usually produces anti-drug antibodies, which represent early indicators for a beneficial clinical outcome.^[14] Furthermore, despite the development of anti-drug antibody responses after the first catumaxomab application cycle a repeated cycle of catumaxomab also leads to a treatment success in recurrent malignant ascites.^[15] Cross-linking leads to the release of cytokines, resulting in manageable adverse effects like fever, nausea and vomiting, that were generally reversible and mainly related to the immunological mode of action (e.g. catumaxomab).^[16] Catumaxomab, which was approved in 2009 for the treatment of

Another way of immunotherapeutic intervention strategies is the exploration of bispecific antibodies with different structures, of which bi-specific T-cell engagers (BiTEs) have been produced since the mid-2000s.^[17]

Production

At first, mouse

Using two different species (mouse and rat) has the advantage that less mismatched antibodies are produced because rat light chains preferably pair with rat heavy chains, and mouse light chains with mouse heavy chains. Single species (mouse/mouse or rat/rat) quadromas, by contrast, produce up to ten different kinds of antibody, most of which have mismatched heavy or light chains, or both.^[18]

References