Avimer
Encyclopedia
Avimers are artificial protein
s that are able to specifically bind to certain antigen
s via multiple binding sites. Since they are not structurally related to antibodies, they are classified as a type of antibody mimetic
. Avimers have been developed by the biotechnology company Avidia, now part of Amgen
, as potential new pharmaceutical drugs.
sequences of 30 to 35 amino acid
s each, connected by linker peptides. The individual sequences are derived from A domains
of various membrane receptor
s and have a rigid structure, stabilised by disulfide bond
s and calcium
. Each A domain can bind to a certain epitope
of the target protein. The combination of domains binding to different epitopes of the same protein increases affinity to this protein, an effect known as avidity
(hence the name).
Alternatively, the domains can be directed against epitopes on different target proteins. This approach is similar to the one taken in the development of bispecific monoclonal antibodies. In a study, the plasma
half-life
of an anti-interleukin 6
avimer could be increased by extending it with an anti-immunoglobulin G
domain.
because of their smaller size. Half-life can be increased by binding them to antibodies.
. The most promising species are linked to a second A domain via a short linker peptide, forming a new library. This process can be repeated several times, yielding avimers with an increasing number of domains.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that are able to specifically bind to certain antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s via multiple binding sites. Since they are not structurally related to antibodies, they are classified as a type of antibody mimetic
Antibody mimetic
Antibody mimetics are organic compounds that, like antibodies, can specifically bind antigens, but that are not structurally related to antibodies. They are usually artificial peptides or proteins with a molar mass of about 3 to 20 kDa...
. Avimers have been developed by the biotechnology company Avidia, now part of Amgen
Amgen
Amgen Inc. is an international biotechnology company headquartered in Thousand Oaks, California. Located in the Conejo Valley, Amgen is the world's largest independent biotech firm. The company employs approximately 17,000 staff members. Its products include Epogen, Aranesp, Enbrel, Kineret,...
, as potential new pharmaceutical drugs.
Structure
Avimers consist of two or more peptidePeptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
sequences of 30 to 35 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s each, connected by linker peptides. The individual sequences are derived from A domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
of various membrane receptor
Membrane receptor
Cell surface receptors are specialized integral membrane proteins that take part in communication between the cell and the outside world...
s and have a rigid structure, stabilised by disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s and calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
. Each A domain can bind to a certain epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
of the target protein. The combination of domains binding to different epitopes of the same protein increases affinity to this protein, an effect known as avidity
Avidity
In proteins, avidity is a term used to describe the combined strength of multiple bond interactions. Avidity is distinct from affinity, which is a term used to describe the strength of a single bond...
(hence the name).
Alternatively, the domains can be directed against epitopes on different target proteins. This approach is similar to the one taken in the development of bispecific monoclonal antibodies. In a study, the plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
of an anti-interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
avimer could be increased by extending it with an anti-immunoglobulin G
Immunoglobulin G
Immunoglobulin G are antibody molecules. Each IgG is composed of four peptide chains — two heavy chains γ and two light chains. Each IgG has two antigen binding sites. Other immunoglobulins may be described in terms of polymers with the IgG structure considered the monomer.IgG constitutes 75%...
domain.
Properties
Avimers with two or three domains can bind to their targets in sub-nanomolar concentrations. They have improved heat stability compared with antibodies, but limited plasma half-lifeBiological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
because of their smaller size. Half-life can be increased by binding them to antibodies.
Production
A library theoretically containing up to 1023 different A domains serves as a starting point for the development of avimers. Domains targeting the desired protein are selected with display techniques such as phage displayPhage display
Phage display is a method for the study of protein–protein, protein–peptide, and protein–DNA interactions that uses bacteriophages to connect proteins with the genetic information that encodes them. Phage Display was originally invented by George P...
. The most promising species are linked to a second A domain via a short linker peptide, forming a new library. This process can be repeated several times, yielding avimers with an increasing number of domains.