Successful development of monoclonal antibodies (mAbs) for therapeutic applications requires identification of mAbs with excellent biophysical properties in addition to potent bioactivities. The most important biophysical properties of mAbs are their solubility and viscosity given their importance to antibody processing, formulation and delivery. However, mAbs also display other complex biophysical properties that frustrate their development, such as formation of soluble aggregates and subvisible particles as well as non-specific interactions with non-adsorptive chromatography columns that can lead to poor recoveries and abnormally long elution times. Here we have investigated the potential of using measurements of antibody self-association obtained using affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) at dilute concentrations (micrograms per mL) for ranking a panel of mAbs in terms of their relative risk for displaying poor biophysical properties at much higher concentrations (milligrams per mL). Interestingly, the biophysical properties of the mAbs (retention time and fractional recovery from a size-exclusion column, solubility and fractional monomer content) displayed modest correlation with each other, as some mAbs with defects in one property (e.g., solubility) failed to show defects in other properties (e.g., fractional monomer content). The ranking of mAbs in terms of their level of self-association obtained by AC-SINS measurements was best correlated with their solubility ranking and modestly correlated with the other properties. However, the correlation was even stronger between the average ranking of the four biophysical properties and the AC-SINS measurements. This suggests that weak self-interactions detected using AC-SINS manifest themselves in different ways and lead to complex biophysical properties. Our findings highlight the limitations of attempting to correlate self-interaction measurements to a single biophysical property. We expect that AC-SINS will be useful for screening mAbs early in discovery to identify variants with reduced risk of displaying suboptimal biophysical properties later in development when processed at much higher concentrations.

Measurements of antibody self-association using affinity-capture self-interaction nanoparticle spectroscopy are correlated with complex biophysical properties

251st National Meeting (2016)

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