title: The application of mathematical modelling to the design of bispecific monoclonal antibodies.
abstract: Targeting multiple receptors with bispecific antibodies is a novel approach that may prevent the development of resistance to cancer treatments. Despite the initial promise, full clinical benefit of this technology has yet to be realized. We hypothesized that in order to optimally exploit bispecific antibody technology, thorough fundamental knowledge of their pharmacological properties compared to that of single agent combinations was needed. Therefore, we developed a mathematical model for the binding of bispecific antibodies to their targets that accounts for the spatial distribution of the binding receptors and the kinetics of binding, and is scalable for increasing valency. The model provided an adequate description of internal and literature-reported in vitro data on bispecific binding. Simulations of in vitro binding with the model indicated that bispecific antibodies are not always superior in their binding potency to combination of antibodies, and the affinity of bispecific arms must be optimized for maximum binding potency. Our results suggest that this tool can be used for the design and development of the next generation of anti-cancer bispecific compounds.
authors.affiliation: a LAP&P , Leiden , the Netherlands.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: van Steeg
authors.affiliation: a LAP&P , Leiden , the Netherlands.
authors.forename: Kirsten Riber
authors.initials: KR
authors.lastname: Bergmann
authors.affiliation: b Antibody Discovery and Protein Engineering, Medimmune, LLC , Gaithersburg , MD , USA.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Dimasi
authors.affiliation: c Oncology Research, MedImmune, LLC , Gaithersburg , MD , USA.
authors.forename: Kris F
authors.initials: KF
authors.lastname: Sachsenmeier
authors.affiliation: d Clinical Pharmacology/ DMPK, MedImmune, LLC , Mountain View , CA , USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Agoram
mesh_terms: D018033:Antibodies, Bispecific / Q000737:chemistry / Q000276:immunology; D003198:Computer Simulation; D018448:Models, Immunological; D008958:Models, Molecular
chemical_list: D018033:Antibodies, Bispecific
keywords: Affinity; Monovalent; avidity; binding; bispecific; limitation; mathematical; model; spatial