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A single molecular descriptor to predict solution behavior of therapeutic antibodies

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Science Advances  05 Aug 2020:
Vol. 6, no. 32, eabb0372
DOI: 10.1126/sciadv.abb0372
  • Fig. 1 Poor solution behavior is prevalent in mAbs.

    Viscosity and opalescence of 59 mAbs at 150 mg/ml in 10 mM histidine·HCl (pH 6.0). Dashed lines indicate threshold values of 30 cP and 12 NTU for viscosity and opalescence, respectively. Antibodies with viscosity ≤30 cP and turbidity ≤12 NTU are designated green; those with viscosity >30 cP are designated tan; and those with turbidity >12 NTU are designated brown. In the inset at the bottom, mAbs were categorized overall as inviscid and clear (green), viscous (tan), or opalescent (brown). Products approved for subcutaneous injection are indicated by asterisks.

  • Fig. 2 Colloidal interactions in dilute solution underlie solution behavior.

    (A) Antibodies arranged in descending order of kD,His values reflecting most repulsive to most attractive. (B) Strip plot of rank-ordered mAbs as arranged in (A). (C) Opalescence versus viscosity of mAbs measured at 150 mg/ml in 10 mM histidine·HCl (pH 6.0). Data points are color-coded according to kD,His ranges as indicated in the figure inset. Dashed lines bordering shaded areas represent threshold values for opalescence (12 NTU; brown) and viscosity (30 cP; tan). Well-behaved mAbs with high kD,His values are clustered in the lower left corner (green). (D) kD,His values for mAbs in each solution property category. A threshold of 20 ml/g is indicated with the dashed line. (E) kD,His values organized by subclass: IgG1 (circles), IgG2 (squares), and IgG4 (triangles). (F) kD,His-NaCl values for mAbs in each solution property category. A threshold of −15 ml/g is indicated with the dashed line. In (A), (B), and (D) to (F), individual mAbs are color-coded according to their solution behavior category: inviscid and clear (green), viscous (tan), or opalescent (brown). In (D) and (F), mean values within each category are indicated by the bold horizontal lines.

  • Fig. 3 Electrostatic repulsion dominates colloidal interactions in dilute solution.

    (A) Twenty-three measured and calculated molecular descriptors arranged in order of decreasing favorable value from left to right. Individual mAbs are identified by the numbers in each box and color-coded according to their solution behavior category: inviscid and clear (green), viscous (tan), or opalescent (brown). The Spearman’s rank order correlation (ρ) for each descriptor with respect to kD,His (row 1) is indicated in the rightmost column. (B) to (F) indicate selected molecular descriptors of mAbs [color-coded as in (A)]: (B) measured pI, (C) measured charge, (D) EHI, (E) Fv-CSP, and (F) Fab/Fc-CSP. (G) to (K) indicate the same descriptors organized by subclass as follows: IgG1 (circles), IgG2 (squares), and IgG4 (triangles). Selection thresholds for measured pI and charge (B and C) are indicated with black dashed lines. Solid horizontal lines in (B) to (K) represent mean values of a descriptor in a given category.

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