• Antibody-Dependent Cell-mediated Cytotoxicity or ADCC is a critical mechanisms underlying the clinical efficacy of therapeutic anticancer antibodies;
  • Granule exocytosis is a major mechanism in Antibody Dependent Cell Mediated Cytotoxicity or ADCC
  • Ligation of the Fc receptor (FcR) stimulation of activated human NK cells stimulates expression of Fas ligand on NK cells facilitates Fas-bearing cancer cell killing.

Over the last decades, Antibody dependent Cell-mediated Cytotoxicity or ADCC has been identified as one of the critical mechanisms underlying the clinical efficacy of therapeutic anticancer antibodies. ADCC is a cell-mediated innate immune response. It is a key effector mechanism by which therapeutic antibodies directed against cell surface targets on cancer cells exert their clinical effect.

The process is mediated through the Fc and iC3b receptor bearing effector cells of the immune system, including natural killer (NK), monocyte, macrophage, and eosinophil.

NK cells are large lymphoid cells exerting cytotoxicity on Immunoglobulin G1 (IgG1) and IgG3 [Link to: Immunoglobulin G (IgG) antibody isotypes]

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The perforin/granzyme (granule exocytosis) pathway is a major mechanism involved in this target cancer cells killing process. This pathway is critical for host mechanisms of defense, including viral clearance and tumor cell killing. [1]

In addition to granule exocytosis, ligation of the Fc receptor (FcR) stimulation of activated human NK cells stimulates expression of Fas ligand (FasL or CD95L, a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family) on NK cells (this is the transcriptional up-regulation of Fas ligand). This, in turn, facilitates Fas-bearing (CD95/APO-1) cancer cell killing.

Furthermore, as resting NK cells become activated, their Fas receptors become competent to deliver autocrine suicide signals. The interaction of Fas ligand on the Fc receptor stimulated NK cells with their Fas receptors can result in apoptosis of the NK cells which critically influences the capacity of these cells to mediate paracrine and autocrine cell death [2].

Antibody Dependent Cell-mediated Cytotoxicity: The Process

  1. An antibody, such as an Immunoglobulin G (IgG), binds to a target cancer cell that has been recognized by specific antibodies. The Fc portion of this antibody is recognized by the Fc receptor of an NK (or PBMC) cell.
  2. NK, large lymphoid cells exerting cytotoxicity on IgG1 or IgG3 opsonized targets by releasing perforin (a cytolytic protein found in the granules of Cytotoxic T lymphocytes or CTLs) and granzymes (toxic cytoplasmic granules)
  3. Upon degranulation, perforin inserts itself into the target cancer cell plasma membrane.
  4. After entering the target cancer cell this process actively lyse (triggers apoptosis)

Example
In approximately 30% of all breast cancers, cells display abnormally high levels of the constitutively active receptor, the human epidermal growth factor receptor 2 or HER2, on their surface. These breast cancers are known as a HER2 positive breast cancer. HER2 can, in this case, be used as a target antigen.

Trastuzumab (Herceptin®; Genentech/Roche) inhibits the growth of HER2-positive breast cancer by the activation of a host tumor response via ADCC [3]

Clinical efficacy
Studies have shown that removal of the fucosylated antibody ingredients from antibody therapeutics elicits high ADCC by evading the inhibitory effects of plasma IgG on FcgammaRIIIa binding (effector side interaction) and of fucosylated antibodies on antigen binding (target side interaction). [4]


References

[1] Grossman WJ, Verbsky JW, Tollefsen BL, Kemper C, Atkinson JP, Ley TJ. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood. 2004 Nov 1;104(9):2840-8. Epub 2004 Jul 6. [Article][PubMed]Link to Article: http://www.bloodjournal.org/…
Link to PubMed: http://www.ncbi.nlm.nih.gov/…
[2] Eischen CM, Schilling JD, Lynch DH, Krammer PH, Leibson PJ. Fc receptor-induced expression of Fas ligand on activated NK cells facilitates cell-mediated cytotoxicity and subsequent autocrine NK cell apoptosis. J Immunol. 1996 Apr 15;156(8):2693-9. [Article][PubMed]Link to Article: http://www.jimmunol.org/cont…
Link to PubMed: http://www.ncbi.nlm.nih.gov/…

[3] Petricevic B, Laengle J, Singer J, Sachet M, Fazekas J, Steger G, Bartsch R et al. Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients. J Transl Med. 2013 Dec 12;11:307. doi: 10.1186/1479-5876-11-307. [Article][PubMed]

Link to Article: http://www.ncbi.nlm.nih.gov/…
Link to PubMed: http://www.ncbi.nlm.nih.gov/…

[4] Iida S, Kuni-Kamochi R, Mori K, Misaka H, Inoue M, Okazaki A, Shitara K, Satoh M. Two mechanisms of the enhanced antibody-dependent cellular cytotoxicity (ADCC) efficacy of non-fucosylated therapeutic antibodies in human blood. BMC Cancer. 2009 Feb 18;9:58. doi: 10.1186/1471-2407-9-58. [Article][PubMed]

Link to Article: http://www.ncbi.nlm.nih.gov/…
Link to PubMed: http://www.ncbi.nlm.nih.gov/…


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ADC Review, Journal of Antibody-drug Conjugates (ISSN 2327-0152) launched in 2013, is designed to serve the needs of a diverse community of individuals including academia, life sciences, pharma, (basic, translational and clinical) research, clinicians/physicians, along with regulatory affairs, government authorities and representatives from payers, and policy makers. The Journal’s content includes peer reviewed research, commentaries, news features, discussions, editorials and blogs on topics relevant to a broad international readership. The Journal also offers a knowledge center (called ADC University) offering the latest and most relevant information about Antibody-drug Conjugates (ADCs), BiSpecific Antibodies, Site Specific Antibody Drug Conjugates, Small Molecule Drug Conjugates (SMDC), and Engineered Antibody Fragments. The purpose of the Journal is to present this information in an understandable and a useful format for all stakeholders.