Introduction to Complement-Dependent Cytotoxicity (CDC) and its Clinical Importa

Posted by Janice on April 29th, 2021

With the development and improvement of modern biotechnology, antibody drugs have become the fastest-growing therapeutic drugs and occupy an important position in the field of biotechnology pharmaceuticals. An antibody (Ab) belongs to the immunoglobulin (Ig) family and is a glycoprotein that binds to an antigen. There are five main types of antibodies expressed in the human body: IgM, IgA, IgD, IgG, and IgE, with the highest content of IgG.

Monoclonal antibodies (mAbs) have become an important class of therapeutics, particularly in the realm of anticancer immunotherapy. The structure of the antibody determines its mechanism of action. The antigen-binding fragment (Fab) and crystallizable fragment (Fc) of monoclonal antibodies allow for high-avidity binding to molecular targets. Its Fab segment can recognize the target of free molecules (VEGF, TNF, etc.) and receptors on cell surface (CD20, CD19, etc.), and determine the specific recognition of foreign invaders such as cancer cells. The Fc segment determines the effector function of the antibody, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). 

CDC is a potent effector mechanism, engaging both innate and adaptive immunity. It is mediated by the binding of the antibody and complement C1q, and then C2-C9 is activated to form a membrane attack complex to exert a lytic effect on target cells. It is one mechanism of action by which therapeutic antibodies or antibody fragments can achieve an antitumor effect.

Over the past decade, a series of CDC-related drugs have been developed since scientists demonstrated that enhanced CDC can improve effector functions of monoclonal antibodies for cancer treatment. A number of anti-tumor antibodies, such as antibodies raised against CD20, CD52, Human Leukocyte Antigen (HLA)‐class II, Carcinoembryonic Antigen (CEA), glycolipid antigens, etc., have been known to induce CDC. In the clinic, CD20 mAbs, rituximab (RTX) and ofatumumab (OFA) have been used with success 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 CDC-enhanced ofatumumab is particularly effective at eliminating B cells. 

In 1964, Paul Terasaki and John McClelland introduced the microlymphocytotoxicity test, known as complement-dependent cytotoxicity assay or simply CDC, which has become the standard serological assay for HLA typing and cross-matching in clinical tissue transplantation. HLA typing and cross-matching play a significant role in organ allocation and optimizing graft utilization in transplantation. CDC assay is used in the daily routine in HLA lab, monitoring patients awaiting solid organ transplantation or hematopoietic stem cell transplantation (HSCT). This method enables either cross matching between recipient and donor using T and B cells or detection and specification of HLA antibodies.

With the help of CDC assays, suitable organ or bone marrow transplant donors can be found more effectively and accurately for the patient. And the CDC crossmatch is an informative test that detects alloantibodies in pre-transplant and post-transplant patients, which may dictate clinical management of transplant patients. In some patients with complex immunology, a careful and judicious use of a battery of immunology tests is of utmost importance to do a safe transplant and to avoid exclusion of a good donor.

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Joined: April 28th, 2021
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