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Effects of Tissue Targeting Bispecifics on Therapeutic Window

Abstract

Objectives: The presence of target receptors in non-target tissues can reduce the therapeutic window for a promising therapy due to toxicity in non-target tissues. Bispecific drugs engineered to bind to highly expressed protein in the desired tissue could broaden the therapeutic window. However, the relative affinities to the targeting protein and disease-related receptor must be tuned to balance the effect of tissue targeting and competitive binding. We explore the effects of this balance with mechanistic pharmacokinetics/receptor occupancy (PK/RO) modeling.

Methods: A mechanistic PK/RO model of a bispecific tissue targeting drug was developed. The model included 4 compartments: a central compartment, a peripheral compartment (to capture antibody PK), an efficacy compartment with both receptor and targeting protein expressed, and a toxicity compartment with only receptor expressed. Two assumptions, that the drug can or cannot bind to targeting protein and receptor simultaneously, were tested. The effect of varying the affinities of the drug to targeting protein and receptor on receptor occupancy (RO) in toxicity and efficacy compartments for single and repeated doses were predicted.

 

This work was initially presented by Applied BioMath. Applied BioMath was acquired by Certara in December 2023.

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