Bispecific Antibodies

VIB-RUG Department of Molecular Biomedical Research

Molecular ImmunoBiotechnology Unit

Antibodies are attractive tools to develop therapeutics.

Here's why:

one can select a specificity to a target of choice, and the antibody will preferentially bind to these cells. In principle, any target exposed to the extracellular environment will work.

human antibodies can now be made to human target molecules: by protein engineering, by selection from synthetic libraries, or by immunization of transgenic mice carrying human antibody genes.

by selecting the right target molecule,

	antibodies can transfer a signal to the cell,
	or can block a receptor for its ligand,
	or it can alarm the immune system by opsonizing the cell, resulting in complement activation or Fc-mediated neutrophile binding.

one can couple extra functions to the antibody, which are then preferentially targeted to a specified cell. Examples of such extra functions are:

	a toxin to kill the cell
	a radioactive compound to sterilize a certain body region
	an enzyme to convert a harmless prodrug to a toxic compound, only at the site of the target cell.
	a signaling molecule such as a cytokine, to locally activate the immune system and mark the target cell as "dangerous"
	a bispecific reagent, to crosslink immune effector cells to the target cells and activate the immune system to clear up the target cell, with a possible effect of vaccination and extra protection.

Using recombinant DNA expression techniques, new antibody molecules can be made, using domains from the parent antibody molecule, with altered properties:

smaller molecules have a better capacity to penetrate into the tissue

complete antibody molecules have a very long serum persistence,

small molecules (<60-80 kDa) are filtered very rapidly through the kidney

Complete antibodies are protected from metabolism by Fc-tail binding to the FcRn receptor

Glycosylation on complete antibodies also prolongs serum persistence

A long serum persistence is a favorable feature when the antibody has a passive function, e.g. capturing a target molecule. However, when the molecule has some toxicity or carries out some activity a long serum persistence is often not wanted. Instead, it would be more preferred to reach a favorable blood/target ratio in a short time. Smaller antibody fragments lacking the Fc-tail have these properties. But when the molecules become too small, they are rapidly removed by kidney filtration, with a half life of about 30 minutes. This results in a poor binding of the reagent to the target cells: simply because the contact time is just too short!

An ideal molecule would have the best of both worlds: good tissue penetration, and a body persistence that is long enough to allow sufficient accumulation at the target site.

Not so long ago, a general disbelieve was notable that antibodies would ever meet the "magic bullet" promise scientist had been talking about for almost a century. Now, antibodies are successfully used in the clinic. Examples are Herceptin® and Rituxan®, for use in cancer therapy (breast cancer and lymphoma resp.).
See here other monoclonals introduced in the clinic.

A large amount of antibodies are now in clinical trails by NIH. In the near future, a major part of FDA licensed biologicals will involve antibodies.