Photo Credit: E_zebolov

The following is a summary of “Engineering Agonistic Bispecifics to Investigate the Influence of Distance on Surface-Mediated Complement Activation,” published in the May 2024 issue of Allergy & Immunology by Hamers, et al.

For a study, researchers sought to develop and understand the effectiveness of monomeric agonists, specifically bispecific nanobodies, in activating the human complement system via the C1 complex, and to identify the critical geometric parameters for optimal C1 activation.

The study utilized DNA nanotechnology and protein engineering to design bispecific nanobodies with controlled linker lengths and flexibilities allowing how linker length, as a metric for antigen and epitope location, affects C1 activation. The experiments focused on comparing the impact of different linker lengths on complement activation, C4b deposition, and membrane lysis.

The findings revealed that the efficacy of complement activation by bispecific nanobodies was significantly influenced by linker length and flexibility. A critical range of end-to-end distances necessary for optimal complement activation. Variations in complement activation were not due to differences in C1 activation or C4 cleavage but rather impacted the deposition of C4b and subsequent membrane lysis.

The study highlighted the importance of geometric parameters, such as linker and hinge design, in enhancing the potency of complement activation for targeted cell killing. The use of DNA nanotechnology to fine-tune the parameters demonstrated the potential of synthetic biology in improving complement system-based therapies. The insights provided a framework for the design and optimization of agonists for effective and targeted complement activation.

Reference: journals.aai.org/jimmunol/article/213/2/235/266922/Engineering-Agonistic-Bispecifics-to-Investigate