Title : Building a better antibody-based medicine: Antibody mimetic
Abstract:
Therapeutic proteins (e.g. monoclonal antibodies, cytokines, and enzymes) are widely used in healthcare. Monoclonal antibodies (particularly IgGs) are an important class of protein based-medicine which tend to aggregate and misfold. Therefore, development of stable IgGs remains one of the key challenges in biotechnology. To extend the utility of IgGs much research is focused to stabilize IgGs as highly concentrated solutions, which can be self-administered by patients. We have developed a novel antibody mimetic which has comparable binding characteristic to IgGs, but appeared to be much less prone to aggregation. IgG antibodies are bivalent molecules with two Fabs (antigen binding fragment) and a fragment crystallisable (Fc). To generate antibody mimetic which is called Fab-PEG-Fab (FpF), two Fabs are conjugated together with poly (ethylene glycol) PEG at a site near where they are bound to the hinge in an IgG (Fig 1). PEG acts as a flexible scaffold between the two Fabs to mimic the natural flexibility of the Fabs in an IgG. A case study of FpF prepared from infliximab, to act as a better antibody-based mimetic for ocular indication will be discussed in this talk. Infliximab is an antibody IgG1 that neutralizes TNF-a and is used off label by systemic administration to treat ocular inflammatory diseases such as uveitis. We prepared the Fab-PEG-Fab (FpFinfliximab) from infliximab for direct intravitreal injection. FpFinfliximab was designed to address side effects caused by antibody degradation and the presence of the Fc. Biacore analysis indicated that infliximab and FpFinfliximab maintained binding affinity for both human and murine recombinant TNF-a, while slower dissociation rate constant observed for FpFinfliximab. No Fc mediated RPE cellular uptake was observed for FpFinfliximab. Both infliximab and FpFinfliximab suppressed inflammation by reducing the number of CD45+ infiltrate cells in the EAU mice model after a single intravitreal injection at the onset of peak disease. Infliximab and FpFinfliximab are equally effective to modulate the acute inflammatory response that characterizes EAU. These results offer an opportunity to develop and formulate FpF molecules designed for single and potentially multiple targets using bi-specific FpFs.
Takeaway Notes:
•Learn about different formats of antibody-based medicine
•Learn on antibody mimetics and the reason for their development
•Learn on bispecific format for antibody-based medicine
•Learn on application of biologics for ocular indication such as ocular inflammation
