A single molecular descriptor to predict solution behavior of therapeutic antibodies

Abstract

Despite the therapeutic success of monoclonal antibodies (mAbs), early identification of developable mAb-drug candidates with optimal manufacturability, stability, and delivery attributes remains elusive. Poor solution behavior, which manifests as high solution viscosity or opalescence, profoundly affects the developability of mAb-drugs. Employing a diverse dataset of 59 mAbs, including 43 approved products, and an array of molecular descriptors spanning colloidal, conformational, charge-based, hydrodynamic, and hydrophobic properties, we show that poor solution behavior is prevalent (>30%) in mAbs and is singularly predicted (>90%) by the diffusion interaction parameter (kD), a dilute-solution measure of colloidal self-interaction. No other descriptor, individually or in combination, was found to be as effective as kD. We also show that well-behaved mAbs, a significant subset of which bear high positive charge and pI, present no disadvantages with respect to pharmacokinetics in humans. Here, we provide a systematic framework with quantitative thresholds for selecting well-behaved therapeutic mAbs during drug-discovery.

Global multi-method analysis of interaction parameters for reversibly self-associating macromolecules at high concentrations

“…Smaller discrepancies in operational k D values are found for mAbs showing self-association only with K D on the order of mM or higher. Thus, high-throughput determination of an operational k D by DLS 12 , 39 , 40 may still be very useful for qualitative screening purpose for the presence of self-association, but alone does not lend itself to quantitative interpretations. This problem will be exacerbated when comparing operational values from different techniques.…”

Comparison of Huggins Coefficients and Osmotic Second Virial Coefficients of Buffered Solutions of Monoclonal Antibodies

“…Clearly, an improved understanding of protein hydration, ion solvation, and dipole–dipole, charge–dipole, and perhaps multipole interactions is required to fully understand the molecular significance of the viscometric interaction parameter k H of antibody solutions. Despite these difficulties, k H along with k D [ 26 , 27 ] provides a useful practical measure of the strength of inter-protein interactions at elevated protein concentrations of direct significance to developing antibody formulations that minimize the solution viscosity for many clinical applications.…”

“…This expression is a natural extension of a previously derived linear relationship [ 24 , 25 ] between the leading order hydrodynamic virial k D coefficient for the collective diffusion coefficient D c and Ψ . This quantity likewise provides a basic measure of solution interparticle particle and is also currently being intensively investigated as a potential predictive measure of the stability of antibody solutions against aggregation [ 26 , 27 ].…”

“…While we are waiting for the development of an effective theory of the properties of antibody solutions, we feel that a focus on B 22 and on corresponding properties greatly dependent on B 22 , such as k H , and the corresponding virial for the collective diffusion coefficient k D [ 26 , 27 ] might provide rational metrics for characterizing inter-protein interaction strength under conditions where near-equilibrium association and relatively good dispersion prevails. This ultimate goal transcends whether the protein data itself quantitively ‘fit’ the theoretical predictions of the coarse-grained model.…”

Calculation of therapeutic antibody viscosity with coarse-grained models, hydrodynamic calculations and machine learning-based parameters

“…In therapeutic antibody development, the syringeability limit is approximately 30 centipoise (cP) for subcutaneous injection. 23 Figure 1 covers a wide range of net charges, from +12 e to +32 e. It is feasible to reduce the viscosity below the syringeability limit by increasing the net positive charges even when the short-range interactions favor self-association at high-protein concentrations because the repulsive interactions of the whole antibody prevent protein association.…”