When a spacecraft docks at the International Space Station, it must ensure a perfect fit to prevent malfunction. Although on a much smaller scale, antibodies produced by our bodies against a foreign invader must also “dock” perfectly on their target to elicit an effective immune response.
In recent years, scientists have co-opted the body’s natural defenses to fight cancer. Called immunotherapy, one example of it uses therapeutic monoclonal antibodies to find and destroy cancer cells.
“Monoclonal antibodies like pertuzumab and trastuzumab are widely used in targeted therapies against HER2-overexpressing breast cancer,” said corresponding author Peter Bond, a Senior Principal Investigator at A*STAR’s Bioinformatics Institute (BII).
Both pertuzumab and trastuzumab inhibit cellular signaling by targeting HER2, a cell-surface receptor upregulated in about 20 percent of breast cancers. Joint corresponding author, Principal Investigator Samuel Gan of the Antibody & Product Development (APD) Lab, also of the Experimental Drug Development Centre (EDDC) and p53 Lab, previously showed that although the trastuzumab IgG subtype bound to HER2 with higher affinity as compared to pertuzumab IgG, pertuzumab IgM conversely showed stronger binding as compared to trastuzumab IgM.
To explain their antibody binding data, the collaborative team used a combination of structural data and modeling to derive complete models of trastuzumab IgM and pertuzumab IgM. They also conducted multiscale modeling and simulations to predict molecular interactions with HER2.
Based on this work, they discovered a protruding surface of the HER2 protein that causes ‘steric clashes,’ or poor binding, with trastuzumab IgM. In contrast, pertuzumab IgM utilized all of its antigen-binding sites with HER2, which resulted in stronger binding.
In laboratory studies, the researchers validated their simulation data by showing that pertuzumab IgM inhibited the proliferation of HER2-positive breast cancer cells more effectively than trastuzumab IgM and pertuzumab IgG.
“There is a need for guidance to ensure maximum success in the rational design of IgM therapeutics,” explained Bond. “Our findings highlight the importance of studying complete antibody-antigen interactions at the molecular level for the evaluation of ‘designer antibody therapies’ that would deliver the most effective and cost-effective outcomes for patients.”
Moving forward, the team envisions that modeling and simulation will be incorporated into the design and selection of immunotherapies against metastatic cancer.