A High-Dimensional Interfacial Wave Assay for Early Biophysical Profiling of Therapeutic Antibodies

Abstract

Therapeutic antibody performance depends not only on sequence and structure, but also on how the molecule responds to physico-chemical perturbations encountered in its environment. Whereas sequence and static structure can be inferred under controlled conditions, behaviour is a conditional, multidimensional response to environment, most directly characterised by applying defined perturbations and quantifying the resulting dynamics. Conventional early-stage developability methods capture isolated dimensions of this response under near-equilibrium conditions, deferring integrated behavioural assessment to late-stage characterisation, when the cost of correction is highest. We introduce Variations in Interfacial Behaviour under Excitation (VIBE), an interfacial wave method implemented via Liquid State Intelligence (LSI), a sensing architecture that transduces molecular perturbations at the air-liquid interface into high-dimensional wave patterns. A colloidal liquid substrate operated near a thermodynamic transition couples small molecular perturbations to large dynamical responses, integrating structural flexibility, charge distribution, and surface hydrophobicity into a single behavioural readout from microgram-scale samples. Applied to antibodies previously characterised by industrial benchmarks, the primary behavioural descriptor, VIBE1, functioned as a high-precision triage tool, flagging candidates carrying multiple biophysical liabilities. In a clinical-stage cohort, the proportion of high-VIBE1 antibodies declined progressively from early trials through approval, and high-VIBE1 candidates showed an elevated clinical failure rate. Concordance analysis against estab-lished methods confirmed that VIBE1 captures a composite signal spanning hydrophobicity, polyreactivity, self-interaction, and thermal stability rather than recapitulating any single conventional readout. These findings establish interfacial wave sensing as a low-material modality for early-stage developability assessment, repositioning molecular behaviour from late-stage validation to discovery-phase characterisation.