Small modular immunopharmaceutical

Structure

scFv: modified single-chain variable fragment

Fc: one half of a fragment crystallizable region

VH: heavy chain variable domain

VL: light chain variable domain

CH2: constant domain 2

CH3: constant domain 3 (effector domain)

Arrows: linker peptide (left) and hinge region (right)

N: N-terminus

C: C-terminus]]

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 region (Fc) and the hinge region of an immunoglobulin G1 (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.

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 screened 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 cells, and purified by chromatography.

References

References

1. TruEmergent: [http://www.truemergent.com/technology/smip-therapeutics/ SMIP Therapeutics] {{webarchive. link. (2011-08-22)
2. (2007). "Targeting CD37-positive lymphoid malignancies with a novel engineered small modular immunopharmaceutical". Blood.
3. (2010). "TRU-015, a fusion protein derived from an anti-CD20 antibody, for the treatment of rheumatoid arthritis". Current Opinion in Molecular Therapeutics.
4. (2009). "TRU-016, a humanized anti-CD37 IgG fusion protein for the potential treatment of B-cell malignancies". Current Opinion in Investigational Drugs.
5. TruEmergent: [http://www.truemergent.com/tru-016/ TRU-016 for the Treatment of B-Cell Malignancies] {{webarchive. link. (2011-08-22)