CRM197

CRM197

Description

CRM197 is a genetically detoxified form of diphtheria toxin. A single mutation at position 52, substituting glutamic acid for glycine, causes the ADP-ribosyltransferase activity of the native toxin to be lost. The structural basis for the lack of CRM197 toxicity has recently been elucidated.

The gene for CRM197 has been cloned into Corynebacterium diphtheriae, the bacteria that produces the native toxin.^[6] Like the wild type toxin, CRM197 is expressed as a secreted protein at relatively low yields (typically <100 mg/L). Corynebacterium expressed CRM197 is available from several sources, including List Laboratories and Sigma-Aldrich. The low yield and high cost of commercially available native CRM197 has led to efforts to produce CRM197 in other bacteria but this has proven a difficult task until recently.

Three companies have succeeded at manufacturing CRM197 as a recombinant protein. Ligand's wholly-owned subsidiary, Pelican (previously Pfenex), a

CRM197 possess a binding site for EGF receptor heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family.[9] As this receptor is overexpressed on cancer cells, there have been efforts to use CRM197 as an anti-cancer therapy.^[10] The cancer immunotherapy company Imugene reported dramatic improvements in antibody titers from its B cell peptide cancer immunotherapy targeting HER2 when it used CRM197 as a carrier protein.[5]

CRM197 is being evaluated as a potential drug delivery fusion protein. The Swiss-based Turing Pharmaceuticals is working on CRM197 fusion constructs with therapeutic proteins of up to 1,000 amino acids in length.[6]

Preclinical studies have shown that CRM197 is also suitable for conjugation and presentation of peptide

In 1971 Tsuyoshi Uchida, in the laboratory of Alwin Pappenheimer at Harvard, used nitroguanidine to create mutants of diphtheria toxin, which were called Cross Reacting Materials, or CRMs.^[14] One of these mutants, called CRM197, interested researchers because its lack of toxicity suggested a better starting material for diphtheria vaccine than the wild-type protein, and the protein was found to enhance the immunogenicity of bacterial polysaccharides.^[15] The pharmaceutical company Wyeth took advantage of this immunogenicity in the 1990s when it conjugated seven polysaccharides from Streptococcus pneumoniae to CRM197 to create the original Prevnar vaccine which was FDA approved in February 2000. A 13-polysaccharides Prevnar was FDA-approved in 2010.^[16] The meningococcal vaccine Menveo, from Novartis, is four Neisseria meningitidis polysaccharides plus CRM197. This vaccine gained FDA approval in 2010.^[17]

References