I came across another (private) MAB company, Biovation Limited. Looks like another possible competitor. Parking some stuff from their website below. Comments from anyone with more technical knowledge would be much appreciated.
nig
"After a number of high profile setbacks, therapeutic antibodies are now beginning to successfully emerge from clinical trials into clinical practice. However, a limitation to clinical effectiveness continues to be the immunogenicity of these antibodies including chimaeric and humanised versions. Antibodies which bind to cellular targets appear to be most prone to immunogenicity consistent with enhanced presentation of processed antibody to the immune system and triggering of immunogenic responses. Whilst humanised and human antibodies were originally thought to provide the answer to the problem of immunogenicity, in practice these antibodies still contain amino acid sequences with potential for recognition by the immune system as foreign, largely due to the process of somatic mutation which is required to achieve useful antibody affinity. Such somatic mutations affect CDRs (complementarity determining regions) and framework segments of the variable regions and, whilst germ-line framework segments can be used in humanised antibodies to reduce the level of somatic mutation, the optimisation of humanised antibody binding usually requires alterations to framework amino acids thus counteracting the benefit of germ-line frameworks. Biovation's DeImmunisation technology produces antibodies from which immunogenic epitopes are removed, including, where appropriate, from CDR's.
"Certain proteins in clinical trials and clinical use also suffer from immunogenicity and therefore methods are needed to reduce or eliminate the risk of immunogenicity against proteins for clinical use. Biovation's DeImmunisation technology provides a method for removing potentially immunogenic regions of proteins.
"The basis for Biovation's DeImmunisation technology is that somatic mutation of antibody variable regions can result in immunogenic amino acid sequences. Therefore, DeImmunisation technology focuses on the removal of these potentially immunogenic sequences. In practice, an effective primary immune response against an injected protein requires the processing of that protein and presentation of foreign peptides by MHC class II molecules ("T cell epitopes") which then stimulate helper T cells. In turn, these helper T cells trigger B cells bearing appropriate antibodies to produce these antibodies which bind to the injected protein.
"As there are no routine biological test systems to screen for human T cell epitopes, Biovation's approach is to identify all human MHC class II-binding peptides and eliminate these from the molecule usually by single amino acid changes. Whilst a number of such peptides will not, in practice, be processed and presented correctly, this cannot be predicted and therefore it is appropriate to eliminate such peptides anyway. Therefore, the focus of the technology is on prediction of MHC class II binding peptides and this involves a combination of searching databases of known T cell epitopes and analysis of peptide binding to MHC class II in silico. The proprietary in silico method, termed "peptide threading" (see below), provides for a range of MHC class II allotypes for which antibody variable region sequences are analysed.
"Antibody DeImmunisation therefore provides for the identification and removal of MHC class II binding peptides from the antibody variable region. This can include removal of peptide sequences within CDRs if loss of binding can be avoided. Where the starting antibody is not human, as an additional precaution to avoid immunogenicity, the surface exposed amino acids in the variable region are changed to the corresponding amino acids in a reference human antibody by a process known as "veneering" which has been licenced by Biovation from the National Institutes of Health, USA. Whilst such veneering may resist the binding of any antibodies which might otherwise bind to the non-human variable region, the removal of T cell epitopes avoids the propagation of any such antibody response. In relation to the antibody constant regions, where the starting antibody is mouse, then human antibody constant regions are provided in the final DeImmunised antibody. DeImmunised antibodies created to date have all retained the full binding affinity and specificity of the starting monoclonal antibody.
""Peptide Threading" is a proprietary method for analysis of the binding of every overlapping peptide sequence in a protein to a range of MHC class II molecules. Using state-of-the art protein modelling technology, models for a variety of MHC class II allotypes have been built from the existing crystal structure of human HLA-DR. Through each of these models, overlapping amino acid sequences of 13 amino acids ("13mers") are threaded and a number of binding calculations are undertaken for each peptide based on the fit and ionic/hydrophobic interactions of each peptide for the MHC class II molecule. In practice, 13mers providing known biologically active T cell epitopes invariably rank at the top of the range of binding scores whilst known inactive peptides rank at the bottom.
"Whilst retention of affinity is not a problem with DeImmunisation technology, affinity of the DeImmunised antibody can be increased if required. Biovation's BioDisplayTM technology coupled with mutagenesis of the DeImmunised variable regions has been successfully applied to increase the affinity of DeImmunised antibodies to greatly exceed that of the starting mouse antibody and such affinity enhancement should therefore be feasible with most antibodies. With human antibodies isolated using Biodisplay technology, parallel affinity enhancement and DeImmunisation are routinely undertaken in order to optimise the therapeutic antibody.
"In addition to antibodies, DeImmunisation technology can be applied to other proteins in order to reduce or eliminate immunogenicity in man. As for antibodies, amino acid sequences which bind to MHC class II can be identified by comparison with databases of known T cell epitopes and by peptide threading and thence eliminated. Also, where a human sequence or structural homologue is available, surface amino acids can be veneered to substitute human residues.
"DeImmunisation in order to create an antibody suitable for Immunotherapy or Diagnostic Imaging. Secondly, partnerships are being sought for specific targets where new human antibodies can be isolated using BioDisplay for subsequent DeImmunisation. Thirdly, partnerships are sought for specific non-human, human or combinatorial proteins where DeImmunisation is required for clinical use.
"DeImmunisation and BioDisplay are rapid technologies which provide, from a starting antibody, a DeImmunised antibody within a five month timeframe or, from a starting antigen, a DeImmunised antibody in a nine month timeframe. Therefore, the transition from lab to the clinic is fast. DeImmunised antibodies are designed to avoid infringement of third party patent claims and therefore can be developed without high licencing costs. " |
