Afucosylated monoclonal antibodies are monoclonal antibodies engineered so that the

oligosaccharides An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sugar ...

in the

Fc region The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune s ...

of the antibody do not have any

fucose Fucose is a hexose deoxy sugar with the chemical formula C6H12O5. It is found on ''N''-linked glycans on the mammalian, insect and plant cell surface. Fucose is the fundamental sub-unit of the seaweed polysaccharide fucoidan. The α(1→3) link ...

sugar units. When antibodies are afucosylated,

antibody-dependent cellular cytotoxicity Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose ...

(ADCC) is increased.

Background

Most approved monoclonal antibodies are of the

IgG1 Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG a ...

isotype, where two N-linked biantennary complex-type oligosaccharides are bound to the Fc region. The Fc region exercises the effector function of ADCC through its interaction with

leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

receptors of the FcγR family. ADCC is important in the efficacy of cancer antibodies, but with many approved cancer antibodies there is less ADCC than could be desired due to nonspecific IgG competing with the drugs for binding to FcγIIIa on

natural killer cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

. Afucosylated monoclonal antibodies overcome this problem through improved FcγIIIa binding.

Approaches

The Swiss company GlycArt Biotechnology developed a system using

CHO cells Chinese hamster ovary (CHO) cells are an epithelial cell line derived from the ovary of the Chinese hamster, often used in biological and medical research and commercially in the production of recombinant therapeutic proteins. They have foun ...

, where the cells were engineered to overexpress an enzyme called

GnTIII Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (, ''N-acetylglucosaminyltransferase III'', ''N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferase III'', ''uridine diphosphoacetylglucosamine-glycopeptide be ...

. The effect of this overexpression is to block the formation of fucosylated oligosaccharides on the expressed antibodies. This technology was first reported in 1999 and was the basis of GlycArt Biotechnology.

Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX S ...

acquired GlycArt in 2005 in order to acquire technology to afucosylate antibodies. GlycArt Biotechnology had been founded in 2000 as a spin-out company of the

Swiss Federal Institute of Technology in Zurich (colloquially) , former_name = eidgenössische polytechnische Schule , image = ETHZ.JPG , image_size = , established = , type = Public , budget = CHF 1.896 billion (2021) , rector = Günther Dissertori , president = Joël Mesot , a ...

. The first commercial product from the GlycArt acquisition was

obinutuzumab Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody, originated by GlycArt Biotechnology AG and developed by Roche as a cancer treatment. It can be used as a first-line treatment for chronic ly ...

, which as Gazyva gained FDA approval in November 2013 for the treatment of

chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...

. Kyowa Hakko Kirin's "Potelligent" platform uses a CHO cell line in which ''

FUT8 Alpha-(1,6)-fucosyltransferase is an enzyme that in humans is encoded by the ''FUT8'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation ...

'' has been knocked out, and which produces antibodies with little to no

in the

. The company gained marketing approval in Japan in April 2012 for a monoclonal antibody drug called

mogamulizumab Mogamulizumab, sold under the brand name Poteligeo, is a humanized, afucosylated monoclonal antibody targeting CC chemokine receptor 4 (CCR4). The U.S. Food and Drug Administration (FDA) approved it in August 2018 for treatment of relapsed or ...

which was developed using the platform. The Company's technology was first reported in 2004.

References

{{reflist Monoclonal antibodies