Paper Title
Design, Engineering and Development of a Novel Cancer Therapeutic MAB to The Human EGFR

The accumulated knowledge of the mechanistic basis of antibody-derived therapeutics and the emergence of advanced and sophisticated technologies to derive safe and targeted biotherapeutics have brought monoclonal antibodies to the top of the biological drug market. Indeed, therapeutic antibodies represent one of the most expanding segments of the biopharmaceutical industry. In this study we developed "MabEGFR/CR2" a "Biobetter" version of the anti-human EGFR Mabs currently available in the market such as "Cetuximab" that has proven to be very successful in the treatment of malignancies such as colorectal and head and neck carcinoma as well as glioma. In the first phase of the development we have raised an anti EGFR/CR domain-specific murine Mab and fully determined its molecular features such as specificity, affinity, DNA and protein sequences including the 6 CDRs. We also showed that this murine anti human EGFR Mab recognizes the native epitope on the surface of tumors cells isolated from various cancer types. In the second phase of the development, we carried out the humanization of "MabEGFR/CR2" by grafting the six CDRs' of the original Mab into human antibody "scaffold" in which we previously engineered the Fc regions to enhance the ADCC function . This humanization method included an affinity maturation step. This step involved a round of site-specific mutagenesis of the CDRs. To predict the mutations that would lead to improved affinity while keeping the specificity, we used computational modeling to generate a homology 3D model of the Mab to study the antigen-binding site. Indeed, such model allowed the visualization of the six CDRs loops and the interactions of the canonical residues modeled to help in selecting the mutations that are more likely to affect the affinity of the antibody. Following the mutagenesis study, we have selected the Mab form that has the highest affinity while retaining the specificity. We are currently working on optimizing the production and purification of "MabEGFR/CR2" from a CHO cell line of and will undertake preclinical assessment phase