A heavy-chain antibody is an
antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
which consists only of two
heavy chains and lacks the two
light chains usually found in antibodies.
In common antibodies, the
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
binding region consists of the variable domains of the heavy and light chains (V
H and V
L). Heavy-chain antibodies can bind antigens despite having only V
H domains. This observation has led to the development of a new type of antibody fragments with potential use as
drugs
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
, so-called
single-domain antibodies
A single-domain antibody (sdAb), also known as a nanobody, is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, it is able to bind selectively to a specific antigen. With a molecular weight ...
.
Discovery
In 1989 a group of biologists led by
Raymond Hamers at the
Free University Brussels investigated the immune system of
dromedaries
The dromedary (''Camelus dromedarius'' or ;), also known as the dromedary camel, Arabian camel, or one-humped camel, is a large even-toed ungulate, of the genus ''Camelus'', with one hump on its back.
It is the tallest of the three species of ...
. In addition to the expected four-chain antibodies, they identified simpler antibodies consisting only of two heavy chains. This discovery was published in ''
Nature
Nature, in the broadest sense, is the physics, physical world or universe. "Nature" can refer to the phenomenon, phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. ...
'' in 1993.
In 1995 a research team at the
University of Miami
The University of Miami (UM, UMiami, Miami, U of M, and The U) is a private research university in Coral Gables, Florida. , the university enrolled 19,096 students in 12 colleges and schools across nearly 350 academic majors and programs, incl ...
found a different type of heavy-chain antibodies in
shark
Sharks are a group of elasmobranch fish characterized by a cartilaginous skeleton, five to seven gill slits on the sides of the head, and pectoral fins that are not fused to the head. Modern sharks are classified within the clade Selachimo ...
s.
In cartilaginous fishes
![Heavy chain and common antibody](https://upload.wikimedia.org/wikipedia/commons/6/6f/Heavy_chain_and_common_antibody.svg)
The immunoglobulin new antigen receptor (IgNAR) of
cartilaginous fish
Chondrichthyes (; ) is a class that contains the cartilaginous fishes that have skeletons primarily composed of cartilage. They can be contrasted with the Osteichthyes or ''bony fishes'', which have skeletons primarily composed of bone tissue ...
es (for example sharks) is a heavy-chain antibody. IgNAR shows significant structural differences to other antibodies. It has five constant domains (C
H) per chain instead of the usual three, several
disulfide bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
s in unusual positions, and the
complementarity-determining region 3
Complementarity-determining regions (CDRs) are part of the variable chains in immunoglobulins (antibodies) and T cell receptors, generated by B-cells and T-cells respectively, where these molecules bind to their specific antigen. A set of CDRs c ...
(CDR3) forms an extended loop covering the site which binds to a light chain in other antibodies. These differences, in combination with the
phylogenetic
In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups o ...
age of the cartilaginous fishes, have led to the hypothesis that IgNAR could be more closely related to a primordial antigen-binding protein than the
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
ian immunoglobulins. To test this hypothesis, it would be necessary to discover IgNAR or similar antibodies in
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s that are phylogenetically still older, like the
jawless fish
Agnatha (, Ancient Greek 'without jaws') is an infraphylum of jawless fish in the phylum Chordata, subphylum Vertebrata, consisting of both present (cyclostomes) and extinct (conodonts and ostracoderms) species. Among recent animals, cyclostomes ...
lamprey
Lampreys (sometimes inaccurately called lamprey eels) are an ancient extant lineage of jawless fish of the order Petromyzontiformes , placed in the superclass Cyclostomata. The adult lamprey may be characterized by a toothed, funnel-like s ...
and
hagfish
Hagfish, of the class Myxini (also known as Hyperotreti) and order Myxiniformes , are eel-shaped, slime-producing marine fish (occasionally called slime eels). They are the only known living animals that have a skull but no vertebral column, a ...
.
Non-vertebrate
Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
s do not have antibodies at all.
Sharks, and possibly other cartilaginous fishes, have
immunoglobulin M
Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...
(IgM) and
immunoglobulin W
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
(IgW) as well, both types with two heavy and two light chains.
In camelids
The only mammals with heavy-chain (
IgG
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 ...
-like) antibodies are
camelid
Camelids are members of the biological family Camelidae, the only currently living family in the suborder Tylopoda. The seven extant members of this group are: dromedary camels, Bactrian camels, wild Bactrian camels, llamas, alpacas, vicuñas, ...
s such as dromedaries,
camel
A camel (from: la, camelus and grc-gre, κάμηλος (''kamēlos'') from Hebrew or Phoenician: גָמָל ''gāmāl''.) is an even-toed ungulate in the genus ''Camelus'' that bears distinctive fatty deposits known as "humps" on its back. C ...
s,
llama
The llama (; ) (''Lama glama'') is a domesticated South American camelid, widely used as a List of meat animals, meat and pack animal by Inca empire, Andean cultures since the Pre-Columbian era.
Llamas are social animals and live with othe ...
s and
alpaca
The alpaca (''Lama pacos'') is a species of South American camelid mammal. It is similar to, and often confused with, the llama. However, alpacas are often noticeably smaller than llamas. The two animals are closely related and can successfu ...
s. This is a secondary development: The heavy chains of these antibodies have lost one of their constant domains (C
H1) and undergone modifications in the variable domain (V
H), both structural elements necessary for the binding of light chains. In one subgroup, the missing C
H1 seems to be replaced by an extended hinge region, as shown in the image.
Despite their different overall structure, camelid heavy-chain antibodies share several properties with IgNAR, for example the extended CDR3 loop and the
conformation of the CDR1. It has been reasoned that these similarities are caused by functional requirements, or
convergent evolution
Convergent evolution is the independent evolution of similar features in species of different periods or epochs in time. Convergent evolution creates analogous structures that have similar form or function but were not present in the last com ...
, rather than a genuine relationship.
About 50% of the antibodies in camelids are of the ordinary mammalian heavy/light-chain type.
It is not known whether any type of animal has only heavy-chain antibodies and completely lacks the common type with two heavy and two light chains.
Heavy-chain camelid antibodies have been found to be just as specific as a regular antibody and in some cases they are more robust. As well, they are easily isolated using the same phage panning procedure used for traditional antibodies, allowing them to be cultured ''
ex vivo
''Ex vivo'' (Latin: "out of the living") literally means that which takes place outside an organism. In science, ''ex vivo'' refers to experimentation or measurements done in or on tissue from an organism in an external environment with minimal ...
'' in large concentrations. Phage-displayed
dromedary camel
The dromedary (''Camelus dromedarius'' or ;), also known as the dromedary camel, Arabian camel, or one-humped camel, is a large even-toed ungulate, of the genus ''Camelus'', with one hump on its back.
It is the tallest of the three species of ...
V
HH libraries have been made for isolating
single-domain antibodies
A single-domain antibody (sdAb), also known as a nanobody, is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, it is able to bind selectively to a specific antigen. With a molecular weight ...
against
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
and other virus infections. The smaller size and single domain make these antibodies easier to transform into bacterial cells for bulk production, making them ideal for research purposes.
[Ghannam, A., Kumari, S., Muyldermans, S., & Abbady, A. Q. (2015). Camelid nanobodies with high affinity for broad bean mottle virus: a possible promising tool to immunomodulate plant resistance against viruses. Plant Molecular Biology, 1-15.]
References
External links
* Wikilite
Biology of immunoglobulin light chains
{{Immune proteins
Antibodies