A Flexible Multiplatform Bioanalytical Strategy for Measurement of Total Circulating Shed Target Receptors: Application to Soluble B Cell Maturation Antigen Levels in the Presence of a Bispecific Antibody Drug

B cell maturation antigen (BCMA) is a membrane-bound receptor that is overexpressed on multiple myeloma cells and can be targeted with biotherapeutics. Soluble shed forms of membrane-associated receptors in circulation can act as a drug sink, especially when it is present in high molar ratio compared to drug concentration, potentially derailing the intended pharmacological mechanism and impacting pharmacokinetic (PK) measurements and efficacious dose predictions. In this study, we present a bioanalytical strategy for assessing dynamic levels of total soluble BCMA before and during treatment with a bispecific antibody targeting BCMA and CD3. Implementation of a ligand binding assay was not successful due to extensive bispecific antibody interference. Instead, we explored two types of immunoaffinity (IA) liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays, one at the protein level and one at the surrogate peptide level. Ultimately, the protein-level IA-LC-MS/MS method was optimized for use in a cynomolgus monkey PK/pharmacodynamic study. In addition, we demonstrated that the method was easily adapted for use with human samples in preparation for translation to the clinic. This work demonstrates the benefit of flexibility and agility in bioanalytical method development in early drug development. Multiplatform suitability assessments enable rapid, resource-sparing identification and qualification of clinically translatable assays. We recommend early adoption of this strategy to provide enough time for critical reagent development and assay validation for analysis of shed targets.