Small modular immunopharmaceuticals, or SMIPs for short, are artificial

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

s that are intended for use as

pharmaceutical drug A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

s. They are largely built from parts of antibodies (immunoglobulins), and like them have a

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may inclu ...

for

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

s that could be used for

monoclonal antibody therapy Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack thos ...

. 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 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 ...

and are now being developed by

Emergent BioSolutions Emergent BioSolutions Inc. is an American multinational specialty biopharmaceutical company headquartered in Gaithersburg, Maryland. It develops vaccines and antibody therapeutics for infectious diseases and opioid overdoses, and it provides m ...

, 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 A single-chain variable fragment (scFv) is not actually a fragment of an antibody, but instead is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of te ...

(scFv), and the rest of the protein can be constructed from the

fragment crystallizable region The fragment crystallizable region (Fc 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 ...

(Fc) and the hinge region of an

immunoglobulin G Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...

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 In biology, a monotypic taxon is a taxonomic group (taxon) that contains only one immediately subordinate taxon. A monotypic species is one that does not include subspecies or smaller, infraspecific taxa. In the case of genera, the term "unispe ...

, meaning they recognize and attach to a single antigen target to initiate their

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

. 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 B-lymphocyte antigen CD20 or CD20 is expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity. In humans CD20 is encoded by the ''MS4A1'' gene. This gene e ...

targeting SMIP under research for

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and ...

, and TRU-016, a

CD37 Leukocyte antigen CD37 is a protein that in humans is encoded by the ''CD37'' gene. Function The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell- ...

targeting potential treatment for

chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, n ...

and other B-cell cancers.TruEmergent
TRU-016 for the Treatment of B-Cell Malignancies

Production

A monoclonal antibody targeting the desired antigen can be developed the classical way, using

hybridoma technology Hybridoma technology is a method for producing large numbers of identical antibodies (also called monoclonal antibodies). This process starts by injecting a mouse (or other mammal) with an antigen that provokes an immune response. A type of whit ...

. 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 (

transfect Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: "transformation" is typically used to desc ...

ed) cells and

screened A projection screen is an installation consisting of a surface and a support structure used for displaying a projected image for the view of an audience. Projection screens may be permanently installed, as in a movie theater; painted on the ...

for clones 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 (CHO) cells are an epithelial cell line derived from the ovary of the Chinese hamster, often used in biological and medical research and commercially in the production of recombinant therapeutic proteins. They have found wid ...

s, and purified by

chromatography In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it through a system ( ...

References

{{Engineered antibodies Monoclonal antibodies