Small modular immunopharmaceutical
Encyclopedia
Small modular immunopharmaceuticals, or SMIPs for short, are artificial protein
s that are intended for use as pharmaceutical drugs. They are largely built from parts of antibodies (immunoglobulins), and like them have a binding site
for antigen
s that could be used for monoclonal antibody therapy
. SMIPs have similar biological half-life and, being smaller than antibodies, are reasoned to have better tissue penetration properties. They were invented by Trubion
and are now being developed by Emergent BioSolutions
, which acquired Trubion in 2010.
(Fc) and the hinge region of an immunoglobulin G
1 (IgG1). Genetically modified cells produce SMIPs as antibody-like dimers, which are about 30% smaller than real antibodies.
Like ordinary monoclonal antibodies, SMIPs are monospecific
, meaning they recognize and attach to a single antigen target to initiate their biological activity. SMIP drug candidates are intended to target antigens with the same specificity and predictable biological activity as monoclonal antibodies. Examples are TRU-015, a CD20
targeting SMIP under research for rheumatoid arthritis
, and TRU-016, a CD37
targeting potential treatment for chronic lymphocytic leukemia
and other B-cell cancers.
for species with useful properties like high binding specificity. The selected protein is multiplied in transfected cells suitable for medium- or large-scale production, for example Chinese hamster ovary cell
s, and purified by chromatography
.
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 intended for use as pharmaceutical drugs. They are largely built from parts of antibodies (immunoglobulins), and like them have a binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
for 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 that could be used for monoclonal antibody therapy
Monoclonal antibody therapy
Monoclonal antibody therapy is the use of monoclonal antibodies to specifically bind to target cells or proteins. This may then stimulate the patient's immune system to attack those cells...
. SMIPs have similar biological half-life and, being smaller than antibodies, are reasoned to have better tissue penetration properties. They were invented by Trubion
Trubion
Trubion was a publicly held biopharmaceutical company that was focused on creating a pipeline of protein-based therapeutic product candidates to treat autoimmune and inflammatory diseases and cancer. Trubion was acquired by Emergent BioSolutions on October 28, 2010...
and are now being developed by Emergent BioSolutions
Emergent BioSolutions
Emergent BioSolutions is a multinational biopharmaceutical company headquartered in Rockville, Maryland. Emergent develops vaccines and therapeutics targeting infectious diseases, oncology and autoimmune disorders. Founded as BioPort Corporation in 1998, the company was named Emergent...
, which acquired Trubion in 2010.
Structure
SMIPs are single-chain proteins that comprise one binding region, one hinge region as a connector, and one effector domain. The binding region is a modified single-chain variable fragment (scFv), and the rest of the protein can be constructed from the fragment crystallizable regionFragment crystallizable region
The fragment crystallizable region is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system...
(Fc) and the hinge region of an 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%...
1 (IgG1). Genetically modified cells produce SMIPs as antibody-like dimers, which are about 30% smaller than real antibodies.
Like ordinary monoclonal antibodies, SMIPs are monospecific
Monospecific antibody
Monospecific antibodies are antibodies that all have affinity for the same antigen. Monoclonal antibodies are monospecific, but monospecific antibodies may also be produced by other means than producing them from a common germ cell.-Hybridoma cell:...
, meaning they recognize and attach to a single antigen target to initiate their biological activity. SMIP drug candidates are intended to target antigens with the same specificity and predictable biological activity as monoclonal antibodies. Examples are TRU-015, a CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
targeting SMIP under research for rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, and TRU-016, a CD37
CD37
Leukocyte antigen CD37 is a protein that in humans is encoded by the CD37 gene.-External links:...
targeting potential treatment for chronic lymphocytic leukemia
Chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
and other B-cell cancers.
Production
A monoclonal antibody targeting the desired antigen can be developed the classical way, using hybridoma technology. The scFv is then constructed from the antibody's variable regions. A large number of different hinge regions and effector domains are taken from libraries of immunoglobulins, and the combined proteins are produced in genetically modified (transfected) cells and screenedHigh-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
for species with useful properties like high binding specificity. The selected protein is multiplied in transfected cells suitable for medium- or large-scale production, for example Chinese hamster ovary cell
Chinese Hamster Ovary cell
Chinese hamster ovary cells are a cell line derived from the ovary of the Chinese hamster. They are often used in biological and medical research and commercially in the production of therapeutic proteins. They were introduced in the 1960s and grow as a cultured monolayer...
s, and purified by chromatography
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....
.