Guiding principles for mechanistic modeling of bispecific antibodies.

System based pharmacokinetic (PK) models can be used to study and predict the distribution of antibody based drugs into target tissues and assess the pharmacobinding (PB) of the drug to the target and the subsequent pharmacodynamic (PD) changes. In the absence of relevant PD readouts, compounded in cases of novel mechanisms, one can rely on binding between the drug and the target, computed as target occupancy (TO), as a relevant biomarker. This approach assumes that at maximum TO across the dosing interval, the drug-target interaction must demonstrate the intended pharmacology. Such analysis can help set laboratory objectives for protein engineers and chemists and guide them to the appropriate design and binding affinity of the molecule. Analysis of mechanistic models to guide affinity optimization against soluble and membrane-bound targets has been done for monoclonal antibodies (mAbs) (Tiwari et al., The AAPS Journal, 2017). However, comparable understanding of bispecific antibodies (BsAb; drugs with two targets, which are either soluble, membrane-bound, or a combination of the two) is still lacking. We propose to extend the work done by Tiwari et al. (2017) to BsAb. We focus on describing a generic BsAb with two membrane-bound targets, and explore the impact of various parameters on the TO of the BsAb to each target. Performed analysis can guide the optimization of dissociation constant (KD) of the BsAb, and can also help in identifying druggable targets. Proposed model can be modified and tailored to specific biologics as needed.