Abstract 1940 Nanobodies are HER 2 Save the Day: The Role of Nanobodies in Combatting HER2 Overexpression

Every year, over 240,000 people in the United States are diagnosed with breast cancer. About 30% of breast cancer cases present an overexpression of the human epidermal growth factor receptor 2 (HER2), which is correlated with the development of breast cancer and more aggressive tumors. These receptors cooperate with other human epidermal growth factor receptors to regulate differentiation and cell growth. We propose the use of nanobodies, single-domain antibody fragments, as a primary treatment for HER2 overexpression. Currently, one of the treatments used to combat HER2 overexpression is anti-HER2 monoclonal antibodies. However, this treatment has many drawbacks. First, the large size of the monoclonal antibodies prevents them from easily binding to smaller-sized antigens and penetrating dense tissues. Many patients who take these drugs for an extended period of time also experience monoclonal antibody resistance. Therefore, physicians commonly prescribe tyrosine kinase inhibitors to combat monoclonal antibody resistance treatments However, many of these drugs can lead to the HER2-TK domain mutating. One emerging treatment is the use of nanobodies, which are single-domain antibody fragments. The smaller size and full antigen-binding capacity of nanobodies make them a promising treatment option. In this poster, we will analyze the properties and molecular interactions of nanobodies that help combat HER2 overexpression. Lamtha et al. used amino acid sequence analysis and residue identification to produce clones of antibodies. VHH17, a nanobody clone, was identified as displaying the most HER2 kinase inhibition by interacting with the phosphate-binding loop, the alpha C helix, and the catalytic loop of HER2-TK. Furthermore, charges and polar residues of the HER2-TK activation loop interacted with the CDR1, CDR2, and CDR3, loops of VHH17. Additionally, VHH17 competitively binds at the ATP-binding site of HER2-TK, leading to VhH17 partially inhibiting kinase phosphorylation, thereby reducing breast cancer cell viability. After penetrating the membrane of breast cancer cells, VHH17 decreased HER2-positive cancer cell viability to a significant extent. In collaboration with the Center for Biomolecular Modeling at 3D Molecular Designs the Mahtomedi MAPS Team used 3-D modeling and printing technology to investigate the binding sites of nanobodies, monoclonal antibodies, and HER2 receptors, in order to understand how nanobodies can help a patient suffering from breast cancer.