Antibody
An antibody (Ab) is the secreted form of a
To allow the immune system to recognize millions of different antigens, the antigen-binding sites at both tips of the antibody come in an equally wide variety. The rest of the antibody structure is relatively generic. In humans, antibodies occur in five classes, sometimes called isotypes:
The term humoral immunity is often treated as synonymous with the antibody response, describing the function of the immune system that exists in the body's humors (fluids) in the form of soluble proteins, as distinct from cell-mediated immunity, which generally describes the responses of T cells (especially cytotoxic T cells). In general, antibodies are considered part of the adaptive immune system, though this classification can become complicated. For example, natural IgM,[5] which are made by B-1 lineage cells that have properties more similar to innate immune cells than adaptive, refers to IgM antibodies made independently of an immune response that demonstrate polyreactivity- they recognize multiple distinct (unrelated) antigens. These can work with the complement system in the earliest phases of an immune response to help facilitate clearance of the offending antigen and delivery of the resulting immune complexes to the lymph nodes or spleen for initiation of an immune response. Hence in this capacity, the function of antibodies is more akin to that of innate immunity than adaptive. Nonetheless, in general antibodies are regarded as part of the adaptive immune system because they demonstrate exceptional specificity (with some exception), are produced through genetic rearrangements (rather than being encoded directly in germline), and are a manifestation of immunological memory.
In the course of an immune response, B cells can progressively
Antibodies are central to the immune protection elicited by most vaccines and infections (although other components of the immune system certainly participate and for some diseases are considerably more important than antibodies in generating an immune response, e.g. herpes zoster).[15] Durable protection from infections caused by a given microbe – that is, the ability of the microbe to enter the body and begin to replicate (not necessarily to cause disease) – depends on sustained production of large quantities of antibodies, meaning that effective vaccines ideally elicit persistent high levels of antibody, which relies on long-lived plasma cells. At the same time, many microbes of medical importance have the ability to mutate to escape antibodies elicited by prior infections, and long-lived plasma cells cannot undergo affinity maturation or class switching. This is compensated for through memory B cells: novel variants of a microbe that still retain structural features of previously encountered antigens can elicit memory B cell responses that adapt to those changes. It has been suggested that long-lived plasma cells secrete B cell receptors with higher affinity than those on the surfaces of memory B cells, but findings are not entirely consistent on this point.[16]
Structure
Antibodies are heavy (~150 kDa) proteins of about 10 nm in size,[17] arranged in three globular regions that roughly form a Y shape.
In humans and most other
Structurally an antibody is also partitioned into two antigen-binding fragments (Fab), containing one VL, VH, CL, and CH1 domain each, as well as the crystallisable fragment (Fc), forming the trunk of the Y shape.[20] In between them is a hinge region of the heavy chains, whose flexibility allows antibodies to bind to pairs of epitopes at various distances, to form complexes (dimers, trimers, etc.), and to bind effector molecules more easily.[21]
In an
Antigen-binding site
The variable domains can also be referred to as the FV region. It is the subregion of Fab that binds to an antigen. More specifically, each variable domain contains three hypervariable regions – the amino acids seen there vary the most from antibody to antibody. When the protein folds, these regions give rise to three loops of β-strands, localized near one another on the surface of the antibody. These loops are referred to as the complementarity-determining regions (CDRs), since their shape complements that of an antigen. Three CDRs from each of the heavy and light chains together form an antibody-binding site whose shape can be anything from a pocket to which a smaller antigen binds, to a larger surface, to a protrusion that sticks out into a groove in an antigen. Typically however only a few residues contribute to most of the binding energy.[3]
The existence of two identical antibody-binding sites allows antibody molecules to bind strongly to multivalent antigen (repeating sites such as
The structures of CDRs have been clustered and classified by Chothia et al.[24] and more recently by North et al.[25] and Nikoloudis et al.[26] However, describing an antibody's binding site using only one single static structure limits the understanding and characterization of the antibody's function and properties. To improve antibody structure prediction and to take the strongly correlated CDR loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities.[27]
In the framework of the immune network theory, CDRs are also called idiotypes. According to immune network theory, the adaptive immune system is regulated by interactions between idiotypes.
Fc region
The
Another role of the Fc region is to selectively distribute different antibody classes across the body. In particular, the
Antibodies are glycoproteins,[30] that is, they have carbohydrates (glycans) added to conserved amino acid residues.[30][31] These conserved glycosylation sites occur in the Fc region and influence interactions with effector molecules.[30][32]
Protein structure
The N-terminus of each chain is situated at the tip. Each immunoglobulin domain has a similar structure, characteristic of all the members of the immunoglobulin superfamily: it is composed of between 7 (for constant domains) and 9 (for variable domains)
Antibody complexes
Secreted antibodies can occur as a single Y-shaped unit, a monomer. However, some antibody classes also form
Antibodies also form complexes by binding to antigen: this is called an
B cell receptors
The membrane-bound form of an antibody may be called a surface immunoglobulin (sIg) or a membrane immunoglobulin (mIg). It is part of the B cell receptor (BCR), which allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation.
Classes
Antibodies can come in different varieties known as isotypes or classes. In humans there are five antibody classes known as IgA, IgD, IgE, IgG, and IgM, which are further subdivided into subclasses such as IgA1, IgA2. The prefix "Ig" stands for immunoglobulin, while the suffix denotes the type of heavy chain the antibody contains: the heavy chain types α (alpha), γ (gamma), δ (delta), ε (epsilon), μ (mu) give rise to IgA, IgG, IgD, IgE, IgM, respectively. The distinctive features of each class are determined by the part of the heavy chain within the hinge and Fc region.[3]
The classes differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table.[18] For example,
Class | Subclasses | Description |
---|---|---|
IgA |
2 | Found in Also found in saliva, tears, and breast milk. |
IgD |
1 | Functions mainly as an antigen receptor on B cells that have not been exposed to antigens.[41] It has been shown to activate basophils and mast cells to produce antimicrobial factors.[42] |
IgE |
1 | Binds to allergens and triggers histamine release from mast cells and basophils, and is involved in allergy. Humans and other animals evolved IgE to protect against parasitic worms, though in the present, IgE is primarily related to allergies and asthma.[43] |
IgG |
4 | In its four forms, provides the majority of antibody-based immunity against invading pathogens.[43] The only antibody capable of crossing the placenta to give passive immunity to the fetus. |
IgM
|
1 | Expressed on the surface of B cells (monomer) and in a secreted form (pentamer) with very high avidity. Eliminates pathogens in the early stages of B cell-mediated (humoral) immunity before there is sufficient IgG.[43][41] |
The antibody isotype of a B cell changes during cell
Light chain types
In mammals there are two types of
In non-mammalian animals
In most
Class | Types | Description |
---|---|---|
IgY | Found in birds and reptiles; related to mammalian IgG.[47] | |
IgW | Found in sharks and skates; related to mammalian IgD.[48] | |
IgT/Z | Found in teleost fish[49] |
Antibody–antigen interactions
The antibody's paratope interacts with the antigen's epitope. An antigen usually contains different epitopes along its surface arranged discontinuously, and dominant epitopes on a given antigen are called determinants.
Antibody and antigen interact by spatial complementarity (lock and key). The molecular forces involved in the Fab-epitope interaction are weak and non-specific – for example
Function
The main categories of antibody action include the following:
- Neutralisation, in which neutralizing antibodiesblock parts of the surface of a bacterial cell or virion to render its attack ineffective
- Agglutination, in which antibodies "glue together" foreign cells into clumps that are attractive targets for phagocytosis
- serum-soluble antigens, forcing them to precipitate out of solution in clumps that are attractive targets for phagocytosis
- membrane attack complex, which leads to the following:
- Lysis of the foreign cell
- Encouragement of inflammation by chemotactically attracting inflammatory cells
More indirectly, an antibody can signal immune cells to present antibody fragments to
Activated B cells differentiate into either antibody-producing cells called plasma cells that secrete soluble antibody or memory cells that survive in the body for years afterward in order to allow the immune system to remember an antigen and respond faster upon future exposures.[50]
At the
Activation of complement
Antibodies that bind to surface antigens (for example, on bacteria) will attract the first component of the
Activation of effector cells
To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate. Since an antibody has at least two paratopes, it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region.[43]
Those cells that recognize coated pathogens have Fc receptors, which, as the name suggests, interact with the
Natural antibodies
Humans and higher primates also produce "natural antibodies" that are present in serum before viral infection. Natural antibodies have been defined as antibodies that are produced without any previous infection,
Immunoglobulin diversity
Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies; their amino acid composition varies allowing them to interact with many different antigens.[55] It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen.[56] Although a huge repertoire of different antibodies is generated in a single individual, the number of genes available to make these proteins is limited by the size of the human genome. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes.[57]
Domain variability
The chromosomal region that encodes an antibody is large and contains several distinct gene loci for each domain of the antibody—the chromosome region containing heavy chain genes (IGH@) is found on chromosome 14, and the loci containing lambda and kappa light chain genes (IGL@ and IGK@) are found on chromosomes 22 and 2 in humans. One of these domains is called the variable domain, which is present in each heavy and light chain of every antibody, but can differ in different antibodies generated from distinct B cells. Differences between the variable domains are located on three loops known as hypervariable regions (HV-1, HV-2 and HV-3) or complementarity-determining regions (CDR1, CDR2 and CDR3). CDRs are supported within the variable domains by conserved framework regions. The heavy chain locus contains about 65 different variable domain genes that all differ in their CDRs. Combining these genes with an array of genes for other domains of the antibody generates a large cavalry of antibodies with a high degree of variability. This combination is called V(D)J recombination discussed below.[58]
V(D)J recombination
Somatic recombination of immunoglobulins, also known as V(D)J recombination, involves the generation of a unique immunoglobulin variable region. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces—known as gene segments (subgenes). These segments are called variable (V), diversity (D) and joining (J) segments.[57] V, D and J segments are found in Ig heavy chains, but only V and J segments are found in Ig light chains. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the genomes of mammals. In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different paratopes, and thus different antigen specificities.[59] The rearrangement of several subgenes (i.e. V2 family) for lambda light chain immunoglobulin is coupled with the activation of microRNA miR-650, which further influences biology of B-cells.
RAG proteins play an important role with V(D)J recombination in cutting DNA at a particular region.[59] Without the presence of these proteins, V(D)J recombination would not occur.[59]
After a B cell produces a functional immunoglobulin gene during V(D)J recombination, it cannot express any other variable region (a process known as allelic exclusion) thus each B cell can produce antibodies containing only one kind of variable chain.[3][60]
Somatic hypermutation and affinity maturation
Following activation with antigen, B cells begin to proliferate rapidly. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation (SHM). SHM results in approximately one nucleotide change per variable gene, per cell division.[61] As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains.
This serves to increase the diversity of the antibody pool and impacts the antibody's antigen-binding
Class switching
Isotype or class switching is a biological process occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG).[59] The different classes of antibody, and thus effector functions, are defined by the constant (C) regions of the immunoglobulin heavy chain. Initially, naive B cells express only cell-surface IgM and IgD with identical antigen binding regions. Each isotype is adapted for a distinct function; therefore, after activation, an antibody with an IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen. Class switching allows different daughter cells from the same activated B cell to produce antibodies of different isotypes. Only the constant region of the antibody heavy chain changes during class switching; the variable regions, and therefore antigen specificity, remain unchanged. Thus the progeny of a single B cell can produce antibodies, all specific for the same antigen, but with the ability to produce the effector function appropriate for each antigenic challenge. Class switching is triggered by cytokines; the isotype generated depends on which cytokines are present in the B cell environment.[65]
Class switching occurs in the heavy chain gene locus by a mechanism called class switch recombination (CSR). This mechanism relies on conserved nucleotide motifs, called switch (S) regions, found in DNA upstream of each constant region gene (except in the δ-chain). The DNA strand is broken by the activity of a series of enzymes at two selected S-regions.[66][67] The variable domain exon is rejoined through a process called non-homologous end joining (NHEJ) to the desired constant region (γ, α or ε). This process results in an immunoglobulin gene that encodes an antibody of a different isotype.[68]
Specificity designations
An antibody can be called monospecific if it has specificity for a single antigen or epitope,
Asymmetrical antibodies
Heterodimeric antibodies, which are also asymmetrical antibodies, allow for greater flexibility and new formats for attaching a variety of drugs to the antibody arms. One of the general formats for a heterodimeric antibody is the "knobs-into-holes" format. This format is specific to the heavy chain part of the constant region in antibodies. The "knobs" part is engineered by replacing a small amino acid with a larger one. It fits into the "hole", which is engineered by replacing a large amino acid with a smaller one. What connects the "knobs" to the "holes" are the disulfide bonds between each chain. The "knobs-into-holes" shape facilitates antibody dependent cell mediated cytotoxicity.
To further improve the function of heterodimeric antibodies, many scientists are looking towards artificial constructs. Artificial antibodies are largely diverse protein motifs that use the functional strategy of the antibody molecule, but are not limited by the loop and framework structural constraints of the natural antibody.[74] Being able to control the combinational design of the sequence and three-dimensional space could transcend the natural design and allow for the attachment of different combinations of drugs to the arms.
Heterodimeric antibodies have a greater range in shapes they can take and the drugs that are attached to the arms do not have to be the same on each arm, allowing for different combinations of drugs to be used in cancer treatment. Pharmaceuticals are able to produce highly functional bispecific, and even multispecific, antibodies. The degree to which they can function is impressive given that such a change of shape from the natural form should lead to decreased functionality.
Interchromosomal DNA Transposition
Antibody diversification typically occurs through somatic hypermutation, class switching, and affinity maturation targeting the BCR gene loci, but on occasion more unconventional forms of diversification have been documented.[75] For example, in the case of malaria caused by Plasmodium falciparum, some antibodies from those who had been infected demonstrated an insertion from chromosome 19 containing a 98-amino acid stretch from leukocyte-associated immunoglobulin-like receptor 1, LAIR1, in the elbow joint. This represents a form of interchromosomal transposition. LAIR1 normally binds collagen, but can recognize repetitive interspersed families of polypeptides (RIFIN) family members that are highly expressed on the surface of P. falciparum-infected red blood cells. In fact, these antibodies underwent affinity maturation that enhanced affinity for RIFIN but abolished affinity for collagen. These "LAIR1-containing" antibodies have been found in 5-10% of donors from Tanzania and Mali, though not in European donors.[76] European donors did show 100-1000 nucleotide stretches inside the elbow joints as well, however. This particular phenomenon may be specific to malaria, as infection is known to induce genomic instability.[77]
History
The first use of the term "antibody" occurred in a text by Paul Ehrlich. The term Antikörper (the German word for antibody) appears in the conclusion of his article "Experimental Studies on Immunity", published in October 1891, which states that, "if two substances give rise to two different Antikörper, then they themselves must be different".[78] However, the term was not accepted immediately and several other terms for antibody were proposed; these included Immunkörper, Amboceptor, Zwischenkörper, substance sensibilisatrice, copula, Desmon, philocytase, fixateur, and Immunisin.[78] The word antibody has formal analogy to the word antitoxin and a similar concept to Immunkörper (immune body in English).[78] As such, the original construction of the word contains a logical flaw; the antitoxin is something directed against a toxin, while the antibody is a body directed against something.[78]
The study of antibodies began in 1890 when
In the 1920s, Michael Heidelberger and Oswald Avery observed that antigens could be precipitated by antibodies and went on to show that antibodies are made of protein.[86] The biochemical properties of antigen-antibody-binding interactions were examined in more detail in the late 1930s by John Marrack.[87] The next major advance was in the 1940s, when Linus Pauling confirmed the lock-and-key theory proposed by Ehrlich by showing that the interactions between antibodies and antigens depend more on their shape than their chemical composition.[88] In 1948, Astrid Fagraeus discovered that B cells, in the form of plasma cells, were responsible for generating antibodies.[89]
Further work concentrated on characterizing the structures of the antibody proteins. A major advance in these structural studies was the discovery in the early 1960s by
Medical applications
Disease diagnosis
Detection of particular antibodies is a very common form of medical
In
Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example ELISA, immunofluorescence, Western blot, immunodiffusion, immunoelectrophoresis, and magnetic immunoassay.[102] Antibodies raised against human chorionic gonadotropin are used in over the counter pregnancy tests.
New dioxaborolane chemistry enables radioactive fluoride (18F) labeling of antibodies, which allows for positron emission tomography (PET) imaging of cancer.[103]
Disease therapy
Targeted
Some immune deficiencies, such as
Prenatal therapy
Rho(D) immune globulin antibodies are specific for human RhD antigen.[112] Anti-RhD antibodies are administered as part of a prenatal treatment regimen to prevent sensitization that may occur when a Rh-negative mother has a Rh-positive fetus. Treatment of a mother with Anti-RhD antibodies prior to and immediately after trauma and delivery destroys Rh antigen in the mother's system from the fetus. This occurs before the antigen can stimulate maternal B cells to "remember" Rh antigen by generating memory B cells. Therefore, her humoral immune system will not make anti-Rh antibodies, and will not attack the Rh antigens of the current or subsequent babies. Rho(D) Immune Globulin treatment prevents sensitization that can lead to Rh disease, but does not prevent or treat the underlying disease itself.[112]
Research applications
Specific antibodies are produced by injecting an
In research, purified antibodies are used in many applications. Antibodies for research applications can be found directly from antibody suppliers, or through use of a specialist search engine. Research antibodies are most commonly used to identify and locate
Antibodies used in research are some of the most powerful, yet most problematic reagents with a tremendous number of factors that must be controlled in any experiment including cross reactivity, or the antibody recognizing multiple epitopes and affinity, which can vary widely depending on experimental conditions such as pH, solvent, state of tissue etc. Multiple attempts have been made to improve both the way that researchers validate antibodies).
Antibody regions can be used to further biomedical research by acting as a guide for drugs to reach their target. Several application involve using bacterial plasmids to tag plasmids with the Fc region of the antibody such as pFUSE-Fc plasmid.
Regulations
Production and testing
There are several ways to obtain antibodies, including in vivo techniques like animal immunization and various in vitro approaches, such as the phage display method.[129] Traditionally, most antibodies are produced by hybridoma cell lines through immortalization of antibody-producing cells by chemically induced fusion with myeloma cells. In some cases, additional fusions with other lines have created "triomas" and "quadromas". The manufacturing process should be appropriately described and validated. Validation studies should at least include:
- The demonstration that the process is able to produce in good quality (the process should be validated)
- The impurities and virusmust be eliminated)
- The characterization of purified antibody (biologicalactivities, contaminants, ...)
- Determination of the virus clearance studies
Before clinical trials
- Product safety testing: Sterility (bacteria and fungi), in vitro and in vivo testing for adventitious viruses, murine retrovirus testing..., product safety data needed before the initiation of feasibility trials in serious or immediately life-threatening conditions, it serves to evaluate dangerous potential of the product.
- Feasibility testing: These are pilot studies whose objectives include, among others, early characterization of safety and initial proof of concept in a small specific patient population (in vitro or in vivo testing).
Preclinical studies
- Testing cross-reactivity of antibody: to highlight unwanted interactions (toxicity) of antibodies with previously characterized tissues. This study can be performed in vitro (reactivity of the antibody or immunoconjugate should be determined with a quick-frozen adult tissues) or in vivo (with appropriates animal models).
- preclinicalsafety testing of antibody is designed to identify possible toxicity in humans, to estimate the likelihood and severity of potential adverse events in humans, and to identify a safe starting dose and dose escalation, when possible.
- Animal toxicity studies: Acute toxicity testing, repeat-dose toxicity testing, long-term toxicity testing
- Pharmacokinetics and pharmacodynamics testing: Use for determinate clinical dosages, antibody activities, evaluation of the potential clinical effects
Structure prediction and computational antibody design
The importance of antibodies in health care and the biotechnology industry demands knowledge of their structures at high resolution. This information is used for protein engineering, modifying the antigen binding affinity, and identifying an epitope, of a given antibody. X-ray crystallography is one commonly used method for determining antibody structures. However, crystallizing an antibody is often laborious and time-consuming. Computational approaches provide a cheaper and faster alternative to crystallography, but their results are more equivocal, since they do not produce empirical structures. Online web servers such as Web Antibody Modeling (WAM)[130] and Prediction of Immunoglobulin Structure (PIGS)[131] enable computational modeling of antibody variable regions. Rosetta Antibody is a novel antibody FV region structure prediction server, which incorporates sophisticated techniques to minimize CDR loops and optimize the relative orientation of the light and heavy chains, as well as homology models that predict successful docking of antibodies with their unique antigen.[132] However, describing an antibody's binding site using only one single static structure limits the understanding and characterization of the antibody's function and properties. To improve antibody structure prediction and to take the strongly correlated CDR loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities.[27]
The ability to describe the antibody through binding affinity to the antigen is supplemented by information on antibody structure and amino acid sequences for the purpose of patent claims.[133] Several methods have been presented for computational design of antibodies based on the structural bioinformatics studies of antibody CDRs.[134][135][136]
There are a variety of methods used to sequence an antibody including
Antibody mimetic
Antibody mimetics are organic compounds, like antibodies, that can specifically bind antigens. They consist of artificial peptides or proteins, or aptamer-based nucleic acid molecules with a molar mass of about 3 to 20 kDa. Antibody fragments, such as Fab and nanobodies are not considered as antibody mimetics. Common advantages over antibodies are better solubility, tissue penetration, stability towards heat and enzymes, and comparatively low production costs. Antibody mimetics have being developed and commercialized as research, diagnostic and therapeutic agents.[146]
Binding antibody unit
BAU (binding antibody unit, often as BAU/mL) is a
See also
- Affimer
- Anti-mitochondrial antibodies
- Anti-nuclear antibodies
- Antibody mimetic
- Aptamer
- Colostrum
- ELISA
- Humoral immunity
- Immunology
- Immunosuppressive drug
- Intravenous immunoglobulin(IVIg)
- Magnetic immunoassay
- Microantibody
- Monoclonal antibody
- Neutralizing antibody
- Optimer Ligand
- Secondary antibodies
- Single-domain antibody
- Slope spectroscopy
- Synthetic antibody
- Western blot normalization
References
- ^ ISBN 978-0-534-42174-8.
- PMID 33957119.
Antibodies (A–D) can recognize virtually any antigen whether large or small, and which can have diverse chemical compositions from small molecules (A) to carbohydrates to lipids to peptides (B) to proteins (C and D) and combinations thereof.
- ^ ISBN 978-0-8153-3642-6.
- PMID 8450761.
- S2CID 35784099.
- PMID 31836872.
- PMID 30273443.
- ISBN 978-0-12-397933-9, retrieved 24 January 2024
- S2CID 205212187.
- PMID 19950420.
- PMID 34952892.
- PMID 26187412.
- S2CID 266752931.
- PMID 28104812.
- PMID 36776392.
- PMID 38228150.
- S2CID 24333875. Archived from the original(PDF) on 2 May 2018. Retrieved 1 May 2018.
- ^ S2CID 30584218.
- PMID 14690046.
- PMID 107164.
- ^ )
- ^ "MeSH Browser – gamma-Globulins". meshb.nlm.nih.gov. Retrieved 18 October 2020.
- PMID 5031329.
- ^
Al-Lazikani B, Lesk AM, Chothia C (November 1997). "Standard conformations for the canonical structures of immunoglobulins". Journal of Molecular Biology. 273 (4): 927–48. PMID 9367782.
- PMID 21035459.
- PMID 25071986.
- ^ PMID 34030577.
- PMID 21937984.
- S2CID 73419807.
- ^ PMID 25578468.
- PMID 9442070.
- PMID 31504525.
- S2CID 12187510.
- PMID 24626930.
- PMID 32029686.
- PMID 8476565.
- ^ ISBN 978-0-7817-3650-3.
- S2CID 38464264.
- PMID 10808163.
- PMID 3518747.
- ^ PMID 16895553.
- PMID 19561614.
- ^ ISBN 978-1-55581-246-1.
- PMID 357078.
- PMID 20651744.
- PMID 20651744.
- PMID 16150486.
- PMID 8622930.
- ^ Salinas, I., & Parra, D. (2015). Fish mucosal immunity: Intestine. In Mucosal Health in Aquaculture. Elsevier Inc. https://doi.org/10.1016/B978-0-12-417186-2.00006-6
- S2CID 27041937.
- ^ PMID 11244038.
- S2CID 46096567.
- ^ Racaniello, Vincent (6 October 2009). "Natural antibody protects against viral infection". Virology Blog. Archived from the original on 20 February 2010. Retrieved 22 January 2010.
- PMID 17176435.
- PMID 1988675.
- PMID 8612345.
- ^ S2CID 2234228.
- ^ Peter Parham. The Immune System. 2nd ed. Garland Science: New York, 2005. pg.47–62
- ^ PMID 14551913.
- S2CID 8579156.
- PMID 11869898.
- PMID 3927822.
- ^ S2CID 37636392.
- PMID 10794054.
- PMID 15522624.
- S2CID 32059768.
- PMID 15496946.
- PMID 16793349.
- ISBN 978-0-444-52763-9.
- PMID 25637431.
- ^ a b Farlex dictionary > polyvalent Citing: The American Heritage Medical Dictionary. 2004
- PMID 20400508.
- S2CID 35243494.
- PMID 10339535.
- S2CID 59603663.
- PMID 28847005.
- PMID 26276629.
- ^ S2CID 222200504.
- PMID 8114766.
- ^ Sauter E (10 November 2018). "New Sculpture Portraying Human Antibody as Protective Angel Installed on Scripps Florida Campus". News & Views. Vol. 8, no. 34. The Scripps Research Institute. Archived from the original on 10 January 2011. Retrieved 12 December 2008.
- ^ Pescovitz D (22 October 2008). "Protein sculpture inspired by Vitruvian Man". boingboing (Blog). Archived from the original on 4 November 2010. Retrieved 12 December 2008.
- ^ Emil von Behring – Biographical. NobelPrize.org. Nobel Media AB 2020. Mon. 20 January 2020. <https://www.nobelprize.org/prizes/medicine/1901/behring/biographical/>
- PMID 20318414.
- PMID 15207826.
- S2CID 31571243.
- PMID 16523537.
- OCLC 3220539.
- ^ "The Linus Pauling Papers: How Antibodies and Enzymes Work". Archived from the original on 5 December 2010. Retrieved 5 June 2007.
- S2CID 40595920. Archived from the original(PDF) on 25 March 2009.
- PMID 13889153.
- PMID 2069946.
- ^ S2CID 54380536.
- PMID 4569769.
- PMID 1343085.
- PMID 11282392.
- PMID 16722325.
- PMID 824647.
- ^ "Animated depictions of how antibodies are used in ELISA assays". Cellular Technology Ltd.—Europe. Archived from the original on 14 June 2011. Retrieved 8 May 2007.
- ^ "Animated depictions of how antibodies are used in ELISPOT assays". Cellular Technology Ltd.—Europe. Archived from the original on 16 May 2011. Retrieved 8 May 2007.
- ^ Stern P (2006). "Current possibilities of turbidimetry and nephelometry" (PDF). Klin Biochem Metab. 14 (3): 146–151. Archived from the original (PDF) on 10 April 2008.
- ^ a b Dean L (2005). "Chapter 4: Hemolytic disease of the newborn". Blood Groups and Red Cell Antigens. NCBI Bethesda (MD): National Library of Medicine (US).
- PMID 33242844.
- PMID 27064381.
- PMID 11244034.
- S2CID 16104816.
- PMID 17287478.
- PMID 12662126.
- S2CID 24924864.
- PMID 10891425. Archived from the originalon 29 April 2010. Retrieved 31 March 2007.
- ^ Ghaffer A (26 March 2006). "Immunization". Immunology — Chapter 14. University of South Carolina School of Medicine. Archived from the original on 18 October 2010. Retrieved 6 June 2007.
- PMID 10805260.
- ^ PMID 12970812.
- PMID 11867282.
- S2CID 12616168.
- S2CID 12785078.
- ^ PMID 15353569.
- PMID 10503210.
- PMID 16483794.
- PMID 9711649.
- PMID 7951745.
- PMID 15937343.
- S2CID 14082678.
- ^ "NOT-OD-16-011: Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications". grants.nih.gov.
- PMID 24032093.
- PMID 26594330.
- PMID 24358895.
- ^ "The Antibody Registry". antibodyregistry.org.
- ^ "Resource Identification Initiative". FORCE11. 14 August 2013. Retrieved 18 April 2016.
- ^ Eberle C (20 February 2023). "Antibody Production simply explained". Retrieved 7 December 2023.
- ^ Archived 17 July 2011 at the Wayback Machine
WAM - PMID 18641403. Archived from the original on 26 November 2010.
Prediction of Immunoglobulin Structure (PIGS) Archived 26 November 2010 at the Wayback Machine - ^ Archived 19 July 2011 at the Wayback Machine
RosettaAntibody - ^ Park H. "Written Description Problems of the Monoclonal Antibody Patents after Centocor v. Abbott". jolt.law.harvard.edu. Archived from the original on 13 December 2014. Retrieved 12 December 2014.
- PMID 29702641.
- PMID 25670500.
- PMID 25153121.
- PMID 16545334.
- PMID 14558135.
- PMID 22186715.
- S2CID 42423655.
- PMID 15595863.
- PMID 19535534.
- PMID 20164058.
- PMID 24874765.
- PMID 27562653.
- PMID 19501012.
- PMID 33770519.
- PMID 34723229.
- ^ Knezevic I (10 November 2021). "Training webinar for the calibration of quantitative serology assays using the WHO International Standard for anti-SARS-CoV-2 immunoglobulin" (PDF). Archived (PDF) from the original on 18 February 2022. Retrieved 5 March 2022. (68 pages)
External links
- Mike's Immunoglobulin Structure/Function Page at University of Cambridge
- Antibodies as the PDB molecule of the month Discussion of the structure of antibodies at RCSB Protein Data Bank
- A hundred years of antibody therapy History and applications of antibodies in the treatment of disease at University of Oxford
- How Lymphocytes Produce Antibody from Cells Alive!