Understanding ADCC and CDC from the Perspective of Rituximab

In the fight against disease, two immune actions have shown great potential as rising stars to light the way of disease treatment—antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

Talking about these two effects, rituximab must be discussed as an oncology drug with a long history. Rituximab is a CD20-specific antibody, a potent drug for non-Hodgkin's lymphoma, which acts through ADCC and CDC to kill tumor cells.

ADCC action takes the stage when this therapeutic antibody binds to antigens on the surface of tumor cells as well as Fc receptors on the surface of immune effector cells, activating immune effector cells such as NK cells, macrophages, neutrophils, etc. Once these cells are activated, they release cytotoxic materials such as perforin and granzyme to the tumor cells or infected cells in close proximity. The follow-up work is done by these toxic materials to disrupt tumor cell membranes, allowing water and electrolytes to enter intracellularly rapidly, leading to cell disintegration and destruction, inducing apoptosis, and finally killing tumor cells.

CDC utilizes a different means, relying on a complex set of immune systems—complement system. However, complex as it is, CDC action is the main mechanism of action of rituximab in killing tumor cells: when the complement protein C1q binds to rituximab, it binds to the corresponding antigen on the cell membrane surface to form a complex, initiating the classical pathway of the complement system. C2-C9 is then recruited to form a membrane attack complex (MAC) that works in concert to tear tumor cells to pieces. This process is similar to the killing process of perforin in the action of ADCC and ultimately leads to apoptosis of tumor cells.

Currently, many studies have demonstrated that glycosylation and amino acid sequence modification of the Fc segment of the antibody can improve ADCC activity. As for CDC efficacy improvement, research has shown that modification of amino acids in the CH2 structural domain, and amino acid adjustment of the hinge region can significantly increase CDC activity.

The success of rituximab has led to a boom in the development of drugs related to ADCC and CDC. Examples include trastuzumab and alemtuzumab. The former is used for the treatment of HER-2 positive breast cancer and the latter for the treatment of chronic B-cell lymphocytic leukemia and multiple sclerosis.

Rituximab is undoubtedly a commercial success, however, by studying the mechanism of action of this antibody, scientists have recognized the important role of ADCC and CDC action in tumor immunity as well as autoimmunity. Supported by the established Afuco™ technology platform, Creative Biolabs aims to optimize clients’ antibody development by end-to-end services covering ADCC-enhanced antibody analysis, expression optimization, recombinant protein production, antibody ADCC/CDC modification design, and cell line development, expecting more ADCC and CDC-related antibody products to create more value for human health.

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