MAB Discovery Technology: A Smart Way to Highly Diverse and Functional Therapeutic Antibodies
Poster Sep 02, 2014
Therapeutic antibodies are discussed as a valuable alternative to classical low molecular drug treatment due to their high target specificity. The high number of antibodies in the clinical development should not delude that there are major challenges in the development of therapeutic antibodies leading to significant attrition rates in regard to (pre-) clinical efficacy but also in regard to technical development. Starting the therapeutic antibody development with a high number of diverse functional antibodies can significantly minimize the risk of failure.
MAB Discovery GmbH installed a process which generates a high number of diverse antibodies reflecting the high diversity of the mammalian immune system. The process focusses on rabbits as a proven source for high affine antibodies and consequent lab automation allowing the handling of high number of samples. Rabbits can be immunized with proteins, cells and/or DNA and their serum can be obtained at multiple time points. B cells will be isolated from serum, FACS sorted and cultivated in such a way that antibody secretion into the cell supernatant is stimulated. Phenotypic screening of the supernatants allows the early identification of functional antibodies. Supernatants of interest can be correlated to the corresponding B cells.
After isolating and sequencing the mRNA from the B cell of interest, information on the antibody amino acid sequence is available. Thus potential hot spots can be identified from early on. Antibodies which fit to the requested profile will be recombinantly produced in HEK cells. The recombinant antibody has a human, clinically proved backbone and is available in sufficient amount to allow further characterization in more sophisticated assay systems. A proprietary LIMS guarantees the correct data management and logistics.
Data are given which demonstrate that this highly integrated process provides diverse antibodies by starting with a high number of B cells and filtering the relevant antibodies by an early-on functional screening.
Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes. The majority of these are located in the intergenic or intragenic regions suggesting that the implicated variants may alter chromatin conformation. This, in turn, is likely to influence the expression of nearby or more remotely located genes to alter beta cell function. At present, however, detailed molecular and functional analyses are still lacking for most of these variants. We recently analysed one of these loci and mapped five causal variants in an islet-specific enhancer cluster within the STARD10 gene locus. Here, we aimed to understand how these causal variants influence b-cell function by alteration of the chromatin structure of enhancer clusterREAD MORE