A Mathematical Model for the Rational Design of Chimeric Ligands in Selective Drug Therapies

Abstract

Chimeric drugs with selective potential toward specific cell types constitute one of the most promising forefronts of modern Pharmacology. We present a mathematical model to test and optimize these synthetic constructs, as an alternative to conventional empirical design. We take as a case study a chimeric construct composed of epidermal growth factor (EGF) linked to different mutants of interferon (IFN). Our model quantitatively reproduces all the experimental results, illustrating how chimeras using mutants of IFN with reduced affinity exhibit enhanced selectivity against cell overexpressing EGF receptor. We also investigate how chimeric selectivity can be improved based on the balance between affinity rates, receptor abundance, activity of ligand subunits, and linker length between subunits. The simplicity and generality of the model facilitate a straightforward application to other chimeric constructs, providing a quantitative systematic design and optimization of these selective drugs against certain cell-based diseases, such as Alzheimer's and cancer.

Designing Cell-Targeted Therapeutic Proteins Reveals the Interplay between Domain Connectivity and Cell Binding

“…Previous studies modeled chimeric cytokine complexes by treating IFN binding as though it were a single event (30). However, the dynamics of signaling via colocalization of two IFNa receptors is substantially different from that of signaling via a single receptor (31,33,41).…”

“…Similarly to the work of Doldán-Martelli et al (30), we use the model previously described by Lauffenburger and Linderman (31) for the binding of two molecules associated with a cell membrane to model the dynamics of IFNa or anti-CD20 scFv binding to IFNAR1, IFNAR2, or CD20, given that the complex is already bound to one of the three. The two membrane constituents must be close enough to one another for simultaneous binding to be geometrically possible, given the linker properties; the rate at which this occurs is referred to as k þ (see Lauffenburger and Linderman (31) for details).…”

“…Complementary oligonucleotide pairs of 15,20,30,35,40, and 45 nucleotides that do not form secondary structures and have stable hybridization at 37 C were designed using NUPACK (34) (see Table S1 for the oligonucleotide sequences). The 5 0 end of the oligonucleotides was first modified with a primary amine via a C 6 linker (purchased from Integrated DNA Technologies, Coralville, IA).…”

Target‐Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation, and Optimal Dosing Strategy

“…In the future, the model and its approximation can be extended with (i) TC effects on target cells, (ii) T cell rebound phenomena, and (iii) integration of local geometrical structures on the cell surface for the cross‐linking binding reactions . Inclusion of geometrical structures leads to mathematical models of the form Eqs.…”

“…Binding kinetics of the BsAb [12][13][14][15][16] are presented in Figure 1a. It is assumed that free BsAb concentration C binds to two targets (e.g., receptors) R A and R B to form BCs, RC A and RC B .…”