PTM-Antibodies - Antibody based therapy is a very promising therapy concept with a rising numbers of approved drugs. In spite of this and the fact there are a lot of antibody-based therapies in the pipelines there is still need for more and better antibodies. The majority of antibodies in clinic today are defined through a “top-down” procedure where diseased tissue is differentiated from healthy tissue with techniques mostly based on the immune responses seen in mice against human antigens.
One way to identify new “epitope” on interesting molecule is to take the opposite way and start with the epitope. Instead we are using a bottom-up procedure starting with epitopes defined through proteomic, glycomic, immunological, proteomic techniques or using “theoretical and educated guesses”. In this way we will increase the number of possible antigens for antibody based targeting. Focusing on PTM (post translational modification) of proteins which harbour multiple possible modifications and selecting changes observed or expected to happen we have a huge repertoire of possible epitopes not covered by defined by existing antibodies. Given the knowledge that modifications such as glycosylation and Advanced Glycation Endproducts (AGEs) very frequently add to protein function and binding this new set of reagents will have a huge potential of binding essential epitopes. We create PTM-epitope libraries, designed through synthetically generated and modified peptides in an array form built from possible variation of modifications. The arrays at the size of a standard microscope glass slide can be used for both selection and screening of antibodies generated from c-DNA libraries and expressed as phage libraries. Thus, We have encountered a new concept of “intelligent designed antibodies” based on analysis of protein crystals between similar antibodies and antigens of our choice and molecular modelling. The structural information from x-ray diffraction is used for modelling and design of l ibraries of improved binders.
The project funded by Danish Research Council and EU-FP7 (GatricGlycoExplorer), is a joint effort between University of Copenhagen (Department of Chemistry) and Lund University (Dept of Laboratory Medicine and Division of Clinical Protein Science & Imaging), several European laboratories and the company SARomics AB (Lund).
Link to EUFP7 GastricGlycoExplorer: www.gastricglycoexplorer.eu