Dr. Hans-Willi Krell, MAB Discovery, Neuried/Munich, Germany
Therapeutic antibodies have been established 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 still major challenges in the development of therapeutic antibodies leading to rather high attrition rates due to poor (pre-) clinical efficacy and technical issues in development. Most antibody programs suffer from a rather limited number of candidates the clinical candidate needs to be selected from. Therefore 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 manipulation 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 peripheral blood samples, single cells will be deposit by FACS technology 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. The striking advantage of the MAB technology is the screening of fully active mabs from the B-supernatants which do not need any further optimization regarding affinity and potency.
After isolating the m-RNA from the corresponding B cell and sequencing its resulting PCR product, information on the antibody amino acid sequence is available which allows the identification of critical amino acids early on and helps to select candidates with the desired properties. 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 lab information and management system 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.