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13.3 — Antibodies
An antibody is a Y-shaped protein about 10 nanometres across. Its two arms grip a specific target; its stem tells the rest of the immune system what to do about it. That two-part design — variable recognition, constant instruction — is why one molecular shape can be adapted to essentially any threat while still being understood by a fixed set of downstream machinery.
Antibodies are now also the fastest-growing class of drugs in medicine, and most of the best-selling medicines in the world are engineered versions of this molecule.
The structure
Four polypeptide chains: two identical heavy chains and two identical light chains, held together by disulfide bridges (Chapter 1.3).
Two functional regions.
The variable region, at the tips of the two arms, formed from parts of both a heavy and a light chain. This is what varies between antibodies, and it is the product of the gene rearrangement in Chapter 13.2.
Within it, three short loops on each chain — the complementarity-determining regions — do almost all the contacting. They form a surface complementary to a small patch on the target, called an epitope.
The constant region, forming the stem. It determines the antibody's class, and it is what other immune components bind to.
And the shape is functional. The hinge between the arms gives flexibility, so an antibody can grip two epitopes at different spacings — including two on separate microbes, sticking them together.
Two binding sites, and this doubles the effective strength enormously. A single arm may bind weakly, and two arms binding at once are far harder to dislodge, because both must let go simultaneously.
What antibodies actually do
Antibodies do not destroy anything. They bind, and binding does five things.
Neutralisation. Physically blocking the part of a virus or toxin that attaches to a human cell. A virus that cannot attach cannot enter. This is the only mechanism that works entirely on its own, without any other component, and it is what vaccine-induced antibody mainly does.
Opsonisation. Coating the target so phagocytes can grip it (Chapter 13.1). Phagocytes have receptors for the antibody stem, so an antibody-coated bacterium is engulfed far more efficiently.
Complement activation. Antibody bound to a surface triggers the classical pathway (Chapter 13.1).
Agglutination. Cross-linking multiple targets into clumps, which are easier to clear and cannot spread.
Antibody-dependent cell-mediated killing. Natural killer cells bind the antibody stem on a coated cell and kill it. This mechanism is central to how several antibody drugs work in cancer.
Note that four of the five require something else to do the actual destroying. The antibody is a labelling system, and its power is in directing the rest of the response precisely.
The five classes
Determined by the constant region, and each class exists for a different situation.
IgG — about 75 percent of circulating antibody.
The main antibody of a secondary response and of long-term protection. Neutralises, opsonises, activates complement.
And it is the only class that crosses the placenta.
That single property has large consequences. A newborn is protected for the first few months by its mother's IgG, transferred mainly in the last trimester — which is exactly why premature babies are more vulnerable, having missed part of the transfer.
It is also why maternal vaccination works. Vaccinating a pregnant woman against pertussis, influenza, tetanus and RSV protects the newborn during the window before its own vaccines take effect. Pertussis vaccination in pregnancy reduces infant whooping cough by around 90 percent, and it is one of the most effective uses of a vaccine there is.
And it explains a problem: maternal IgG interferes with the infant's own vaccine responses, which is part of why the childhood schedule starts at 6 to 8 weeks rather than at birth, and why measles vaccine is given later than most.
IgM — about 10 percent.
The first antibody made in a new response, and it is a pentamer — five Y units joined in a ring, giving ten binding sites.
Each individual site binds relatively weakly — this is antibody made before affinity maturation has had time to work — but ten weak grips together are formidable. It is exceptionally good at agglutination and at activating complement.
And its timing makes it diagnostically valuable. IgM against a pathogen means a recent or current infection; IgG alone means past infection or vaccination. This single distinction underlies a large number of blood tests.
IgA — about 15 percent of circulating antibody, and by far the most produced overall.
You make more IgA per day than all other antibody classes combined — around 3 to 5 grams, because it is secreted onto every mucosal surface.
It is the antibody of the gut, airways, tears, saliva and breast milk, and it works mostly by neutralisation, preventing organisms from attaching to the epithelium in the first place.
And breast milk IgA is a genuinely elegant arrangement. Colostrum is exceptionally rich in it, and it is not absorbed — it coats the infant's gut and works locally. The mother's mucosal immune system samples the environment she and the baby share, and secretes antibody against exactly the organisms in it. It is a targeted, continuously updated delivery of protection to the surface where the infant is most vulnerable.
IgE — the smallest amount by far, and it causes the most trouble.
Circulating levels are minute — thousands of times lower than IgG. Almost all of it is bound to mast cells rather than free in the blood.
Its evolved role is defence against parasitic worms. Its clinical importance in wealthy countries is allergy, where the same machinery reacts to pollen and peanuts (Chapter 13.6).
IgD — on the surface of naive B cells, and its function remains incompletely understood, which is worth saying rather than inventing one.
Class switching
A B cell can change which class it makes while keeping exactly the same specificity.
The mechanism is direct: the DNA between the variable region gene and the desired constant region gene is cut out and discarded. It is irreversible — a cell that has switched to IgG cannot go back to IgM.
Which class it switches to is decided by the cytokines the helper T cell provides, so the T cell effectively chooses the weapon for the situation: IgA for a mucosal threat, IgG for a systemic one, IgE for a parasite.
Monoclonal antibodies
This is where the chapter connects to modern medicine most directly.
A natural immune response is polyclonal — many B cell clones producing antibodies against many epitopes on the same target.
A monoclonal antibody comes from a single clone: every molecule identical, binding one epitope.
Georges Köhler and César Milstein produced the first in 1975 by fusing an antibody-producing B cell with a myeloma cell, creating a hybrid that both made a specific antibody and divided indefinitely. They shared the Nobel Prize in 1984 — and, notably, did not patent the technique.
Early monoclonals were made in mice and had a fatal flaw: the human immune system recognised them as foreign and destroyed them, often within days, and sometimes with a severe reaction.
The solution was progressive humanisation, and it is written into the drug names.
| Suffix | Origin |
|---|---|
| -omab | Fully mouse |
| -ximab | Chimeric — mouse variable, human constant |
| -zumab | Humanised — only the binding loops are mouse |
| -umab | Fully human |
So the name tells you the generation. Infliximab is chimeric; trastuzumab is humanised; adalimumab is fully human.
And what they can do covers a remarkable range:
Block a signal — adalimumab and infliximab bind TNF-alpha, a central inflammatory cytokine, and transformed rheumatoid arthritis, Crohn's disease and psoriasis.
Block a receptor — trastuzumab binds HER2 on breast cancer cells (Chapter 1.8).
Deplete a cell type — rituximab binds a marker on B cells and removes them, used in lymphoma and in autoimmune disease.
Release the brakes on T cells — checkpoint inhibitors, which are Chapter 19.7.
Deliver a toxin — antibody–drug conjugates, carrying a chemotherapy payload to the cell that displays the target and nowhere else.
Neutralise a pathogen — monoclonal antibodies against RSV, given to infants, and against COVID-19.
Neutralise a venom or toxin — including digoxin overdose, where the antibody binds the drug directly.
And bispecific antibodies grip two things at once — typically a cancer cell with one arm and a T cell with the other, physically dragging the killer into contact with the target.
Their limitations are worth stating honestly. They are proteins, so they cannot be swallowed (Chapter 12.1) — all are injected or infused. They are expensive to manufacture. Most do not cross the blood–brain barrier (Chapter 11.10), which is a major obstacle in neurological disease. And they can provoke an immune response against themselves, reducing effectiveness over time.
Antibodies as tests
Their specificity makes them the basis of most of diagnostic medicine.
Blood grouping — Chapter 13.7.
Pregnancy tests — antibodies against hCG (Chapter 4.3), in a lateral flow strip.
Lateral flow tests generally — the format made universally familiar by COVID-19. A sample flows along a strip; if the target is present it is captured by antibodies at a line, producing a coloured band. Fast, cheap, and less sensitive than laboratory methods, which is the trade-off.
ELISA — the laboratory standard for measuring almost anything in blood, using an antibody linked to an enzyme that produces a colour change.
Immunohistochemistry — labelled antibodies applied to a tissue section, showing which proteins a tumour expresses. This is how a pathologist determines whether a breast cancer is HER2-positive, and therefore whether trastuzumab will work.
Flow cytometry — labelled antibodies used to count and sort cells. This is how a CD4 count is measured in HIV (Chapter 17.9).
Passive immunity
Giving antibodies directly, rather than provoking their production.
Immediate protection, and no memory — it lasts only as long as the antibodies do, typically weeks to a few months.
Uses:
Post-exposure prophylaxis. Rabies immunoglobulin given alongside the vaccine after a bite provides immediate protection during the two weeks before the vaccine response develops — and rabies is essentially 100 percent fatal once symptoms begin, so that gap matters absolutely (Chapter 23.9). Also for tetanus, hepatitis B and varicella in vulnerable contacts.
Anti-D in pregnancy — Chapter 13.7.
Antivenom — antibodies raised in horses or sheep against snake or spider venom (Chapter 23.9).
Replacement in immunodeficiency — regular immunoglobulin infusions for people who cannot make their own antibody, which converts a fatal condition into a manageable one.
And immunoglobulin in high doses is used as a treatment in its own right in several autoimmune conditions, including Guillain–Barré syndrome and immune thrombocytopenia, by mechanisms that are still only partly understood.
Historically, convalescent serum from recovered patients was a mainstay before antibiotics — diphtheria antitoxin was the first effective treatment for a bacterial disease, and it won the first Nobel Prize in Medicine in 1901. Convalescent plasma was tried extensively for COVID-19 and performed poorly in trials, which is a useful reminder that a plausible mechanism does not guarantee a clinical effect.
What the next page fixes
Antibodies and cells do the specific work. Chapter 13.4 covers the general response that accompanies all of it — inflammation and fever, why they feel unpleasant, why they are useful, and when suppressing them helps and when it does not.