Table 3.

Opportunities for translational and clinical pharmacology in drug development for BsAbs

Functional areas	Question	Possible approaches
Bioanalytical	What are the key fundamental points in selecting a bioanalytical strategy and optimizing the assay for BsAb?	The key rationale is around what to measure for interrogating the exposure response relationship (or safety) of the BsAb. If bifunctional form assay is not available, subsequent assay risk assessment should be considered. There is a timing aspect as well. The approaches are then dictated often by the nature of the BsAb which then can steer towards an LBA as appropriate or LC‐MS for example. The method optimization in terms of what are measured (free, partially bound or total) may be required along with program progression during development.
Preclinical and translational	What are the considerations for the receptor occupancy calculation applied in dose determination for BsAbs?	It is dictated by the affinity and avidity of the BsAbs with the target and any prior information from the mAbs agent.
	What is the basis of selecting the dose and dosing regimen for the FIH study?	The doses are selected from the dose range finding studies in cynomolgus monkeys using MABEL approach. PKPD modeling is performed with preclinical studies and in vitro cytotoxicity data to project the FIH doses.
	What are the considerations for the PD end points that can influence the optimal dose and dosing regimen decision?	The time points when samples are collected to measure PD. The source of the samples (e.g. surrogate tissue or diseased tissue) in which the PD is measured. Measuring PD that is specific to each side of a bispecific molecule and understanding how each one relates to the overall purpose of the PD measure and intended use.
	How does modeling and simulation inform the selection and design of BsAbs?	M&S approaches can elucidate the conditions under which the BsAb modality is superior to a traditional combination therapy and inform the design of a BsAb molecule with optimal characteristics for efficacy.
Clinical	What is the rationale for determining doses in combination treatment involving BsAbs as one of the therapeutics?	The rationale is based on the prior knowledge of clinical data with individual targets, toxicity and efficacy studies, and may be different than the equivalent combination of individual molecules due to factors such as avidity.
	How are DDI studies mitigated?	Based on the known existing potential and interactions with the individual targets, in vitro data and PBPK modeling.
	How are safety and efficacy end points selected?	The efficacy and safety end points may be specific for a BsAb and may not be applied horizontally across all the existing BsAbs. This can often vary from molecule to molecule.