30.09.2021 duration: 4 min

Antibody-Dependent Cellular Cytotoxicity (ADCC) – definition, mechanism & application

Antibody-dependent cellular cytotoxicity (alternatively antibody-dependent cell-mediated cytotoxicity, or ADCC) is a key process of the immune system’s arsenal to ward off cancerous cells and infections. 

When a pathogenic cell is recognized and covered by specific antibodies, it becomes a target for effector cells. Natural killer cells will capture target cells, inject them with cytotoxic factors and ultimately lyse it to harmless fragments. 

Domestication of this mechanism is of high interest in the fields of medicine, biotechnology and life-sciences, enabling the development of profitable products.

Definition: ADCC, afucosylation & ADCC enhanced antibodies

First, a few definitions:

ADCC

ADCC stands for Antibody-Dependent Cellular Cytotoxicity and is a mechanism of the adaptive immune system against pathogenic cells and microbes. 

The definition of ADCC is the process of antibodies recognizing and binding to pathogens, essentially covering their surface to highlight them to specialized blood cells termed natural killer cells (NK cells). NK cells in turn kill those intruders.

ADCC enhanced antibodies

ADCC enhanced antibodies are a special class of antibodies that lead to stronger ADCC responses of the immune system. 

Compared to normal antibodies, ADCC enhanced antibodies have a modified glycosylation pattern that lacks fucose. This is the signal for NK cells to step up their cytotoxic activity.

Afucosylation & afucosylated antibodies

The intentional manipulation of antibodies to have them lack fucose is termed afucosylation. Such afucosylated antibodies are typically manufactured by recombinant technology in mammalian cell lines. 

They hold high promise as novel therapeutics against cancer and infectious diseases and hence are in high demand in discovery and development research.

The mechanism of cell-mediated immune defense

Antibody-dependent cellular cytotoxicity, also termed antibody-dependent cell-mediated cytotoxicity (ADCC) is an important weapon in the immune system’s arsenal to fight cancerous and infected cells.

The process has been described by US and Korean scientists in “Antibody Fc – Linking Adaptive and Innate Immunity in 2014”.​1​

The mechanism relies on immunoglobulins (IgG) that bind to the target cell’s surface with their highly specific antigen binding sites. The other end of the antibodies contains a glycosylated region that represents binding sites for effector cells, mostly natural killer cells.

A class of Fc receptors on the surface of NK cells, termed CD16 receptors, binds to these antibodies, which results in cross-links between CD16 receptors. Subsequently, a cascade of signal transduction pathways is put in motion to activate NK cells.

Upon activation, NK cells release granules filled with cytotoxic factors, termed granzymes and perforin onto the target cell. Perforin inserts into the target cell’s membrane and forms pores through which granzymes can enter the inside of the target cell. 

Granzymes are protease proteins that attack target cells from the inside, leading to cell death. Ultimately, the NK cell lyses the pathogenic target cell into harmless fragments that are digested and recycled by the body.

ADCC mechanism
  1. Antibodies bind to target cell and cover its surface
  2. NK cells recognize the covered target cell through the CD16 receptor
  3. CD16 receptors cross-link, leading to NK cell activation
  4. Release of cytotoxic granules (containing perforin and granzymes) towards the target cell. Perforin inserts into target cell’s membrane and forms pores. Then granzymes enter the target cell and activate cytotoxic pathways, leading to cell death.
  5. NK cell detaches from killed target cell and is ready to attack another target

Application of Antibody-dependent cellular cytotoxicity

Natural killer cells are very potent key players in the body’s fight against cancerous cells and infections

One of their virtues is that they are less discriminate in antibody-dependent cellular cytotoxicity (ADCC) than the immune complement system, since they can be activated by antibody binding, in contrast to specific antigen binding. 

Hence, their therapeutic use by means of ADCC holds high promise in broad fields of medicine and medical research applications.

Numerous monoclonal therapeutic antibodies have been shown to mediate their effects partially or predominantly via NK cell activation through antibody-dependent cell cytotoxicity (ADCC): 

  • Rituximab: solid tumours
  • Trastuzumab: solid tumours
  • Daratumumab: multiple myeloma
  • Isatuximab: multiple myeloma

In recent years, novel therapeutic recombinant antibodies have been engineered to exhibit enhanced ADCC activity.

Interested in recombinant antibodies?

    ADCC enhanced antibodies

    ADCC enhanced antibodies are recombinant antibodies that are optimized to exhibit increased antibody-dependent cellular cytoxicity.

    Antibody-dependent cell-mediated cytotoxicity is mediated through binding of NK cell’s CD16 receptors to the Fc region of antibodies. 

    It has been shown in vitro that lack of fucose in the Fc region leads to stronger binding of CD16 receptors, hence shutting out non-specific competition with other antibodies and increasing the ADCC response.

    Intentional production of recombinant antibodies that lack fucose (afucosylation) for discovery research applications has delivered evidence that strengthens these expectations.

    These findings are highly promising for the development of better treatments for cancer and infections. ADCC enhanced antibodies show two key benefits over conventional therapeutic antibodies:

    • increased potency: smaller amounts of antibodies yield equivalent responses
    • less side-effects: smaller amounts of antibodies lead to less off-target effects

    The production of afucosylated monoclonal antibodies relies on the attachment of fucose-lacking oligosaccharides to the antibodies in host cells. 

    The most effective way to achieve this, is the use of high yielding cell lines that are genetically engineered to have enzymes that block the incorporation of fucose into expressed antibodies. One embodiment of this approach, namely the use of highly advantageous CHO cell lines concurrent with ProBioGen GlymaxX® technology, is used by evitria with large success.

    1. 1.
      Gómez Román VR, Murray JC, Weiner LM. Antibody-Dependent Cellular Cytotoxicity (ADCC). In: Antibody Fc. Elsevier; 2014:1-27. doi:10.1016/b978-0-12-394802-1.00001-7
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