Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors
Fig 1
Bivalent antibody binding model antibodies, rate constants, and reactions.
A, Monoclonal (mAb) and bispecific (BsAb) antibodies simulated in our computational model. Tocilizumab is a recombinant humanized mAb with two anti-IL-6Rα (denoted anti-IL-6R) binding domains; 10H2 is a mAb with two anti-IL-8RB (denoted anti-IL-8R) binding domains; BS1 is an anti-IL-6Rα/anti-IL-8RB BsAb synthesized from the binding domains of tocilizumab and 10H2 by combining the knobs-into-holes and single-chain Fab methodologies. B, Schematic of the IL-6Rα/IL-8RB/BS1 antibody-binding model kinetics. BS1 can bind to either IL-6Rα or IL-8RB, and, having done so, the BS1-receptor complex can then bind to the other receptor. kon,6R and kon,8R describe the association rates for the formation of binary antibody-receptor complexes, and kon,6R* and kon,8R* describe the association rates for the formation ternary receptor-antibody-receptor complexes. The same koff,6R and koff,8R rate constants are used for the dissociation of both the binary and the ternary complexes. Schematics for the two monoclonal antibodies, tocilizumab and 10H2, are included in the Supporting Information (S1 Fig). C, Simplified view of the schematic in B illustrates how the reactions form a thermodynamic cycle. The reactions can proceed in a clockwise or counter-clockwise manner to return back to the starting reactants, forming a cycle with a net free energy change of 0. This figure was created with BioRender.com.