| Abstract | Advances in genomics and antibody engineering have enabled the development of an innovative class of targeted therapies, namely therapeutic antibodies, for the treatment of diseases with significant unmet medical needs such as cancer. Therapeutic antibodies represent one of the largest and fastest growing classes of medications. The NRC has built a chain of cutting edge technology platforms needed to discover, engineer and produce therapeutic monoclonal antibodies with the goal of partnering with industrial and academic centers to advance research and development of this important class of therapeutics.
Target Identification- To establish and validate the technology platforms, tumor targets for candidate therapeutic antibody production were identified using a combination of proteomics, transcriptomics and bioinformatic approaches. Out of these lists, approximately 40 tumor targets were selected (known therapeutic antibody targets were excluded), and over 3,000 antibodies of mouse and camelid origin were then generated against these targets.
Antibody generation- Once identified, the recombinant target protein of interest was produced using the NRC's high efficiency cell expression platforms in CHO or HEK293 cells and purified protein was used for immunization or panning. For targets which were difficult to express or purify, the capabilities for direct immunization with plasmid DNA constructs were utilized. Clone selection was carried out by ELISA and typically 50 antibodies/target were identified for further characterization.
Antibody characterization and validation- The affinities of the antibodies were determined by SPR biosensor analysis. Reverse phase protein arrays and Western blot analysis on protein mixes and cell line extracts allowed the characterization of the specificity of the antibodies. SPR-based epitope binning was carried out in order to characterize the diversity of the antibody collections and to enable the selection of representative antibodies from each epitope bin for further analysis. Select antibodies were assessed in appropriate cell-based assays for prioritization based on function.
Therapeutic antibody Optimization, Bioprocessing and Biomanufacturing- Therapeutic antibodies selected for development can be further optimized using antibody engineering technologies to humanize them and/or modify their glycosylation patterns to improve their effector function, pharmacokinetics, solubility and stability as well as reduce their immunogenicity. The NRC platform for large scale protein production has the capacity to manufacture up to 500 g of commercial grade antibody using serum free, low endotoxin media in a cGMP certified CHO cell line which is ready for transfer to CMOs or other industrial partners. |
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