Antibodies and small molecule drugs

Immunoglobulin architecture

Y-shaped molecules with variable antigen-binding regions and constant Fc regions.

Five classes of immunoglobulins

IgG, IgM, IgA, IgD, IgE.

IgG properties

Most abundant serum antibody (80%); monomeric; long-lived; used for therapeutics.

IgM properties

Pentameric; first antibody produced in immune responses; effective against microorganisms.

IgA properties

Major antibody in secretions (tears, saliva, milk); usually dimeric.

IgE role

Important in allergy and anti-parasitic responses.

Fc region function

Interacts with immune cells and complement; mediates phagocytosis and cytotoxicity.

FcRn receptor

Binds IgG and protects it from degradation, extending its half-life.

Influenza haemagglutinin neutralisation

Antibodies block the sialic-acid binding site and prevent viral entry.

Induced fit in antibody binding

Antibody H3 loop alters shape to bind antigen tightly.

Use of antibodies in research

Western blots, immunohistochemistry, immunoprecipitation.

Polyclonal antibodies

Mixture of antibodies from many B cells recognising multiple epitopes.

Monoclonal antibodies

Identical antibodies recognising a single epitope, produced from hybridomas.

Hybridoma technology

Fusion of B lymphocytes with myeloma cells to generate immortal antibody-producing cells.

HAMA response

Human anti-mouse antibody response that reduces effectiveness of murine antibodies.

Chimeric antibodies

Mouse variable regions fused to human constant regions to reduce immunogenicity.

Humanised antibodies

Mouse CDR loops grafted onto human antibody frameworks to create human-like antibodies.

Fully human antibodies

Produced from transgenic mice or phage display using human gene repertoires.

Phage display

Technology in which antibodies are displayed on phage surfaces for selection by antigen binding.

Humira example

Fully human anti-TNF antibody generated by phage display.

HER2 and trastuzumab (Herceptin)

Trastuzumab binds HER2, blocking signalling and marking cells for destruction.

Cetuximab mechanism

Blocks EGF binding site on EGFR, keeping receptor inactive.

Pertuzumab and panitumumab

Additional anti-EGFR pathway antibodies from hybridoma or transgenic technologies.

Small molecule drugs

Used to inhibit intracellular signalling components, especially kinases.

Tarceva mechanism

Competes with ATP at EGFR kinase active site; exploits induced-fit mechanism.

Vemurafenib mechanism

Inhibits mutant Raf kinase in melanoma; designed by fragment-based screening.

Fragment-based drug design

Screening of small chemical fragments and elaborating them to increase affinity and specificity.

Summary of therapeutic strategies

Antibodies block extracellular targets; small molecules inhibit intracellular enzymes.