Figure 5.
Ablation of FVIII C1 and A3 disulfide bonds changes affinity for patient anti-FVIII drug antibodies. (A) Ribbon representation of the AlphaFold structure of human VIII lacking the unstructured B domain. The domains to which a panel of 4 patient-derived anti-FVIII drug antibodies bind (BOIIB2, KM41, LE2E9, and BO2C11) are shown. The residues that encompass the epitopes for the antibodies are shown as dots (see Table 1 for residue numbers) and the disulfide bond cysteines as yellow spheres. The red spheres are the cysteines that have been replaced with alanine. (B) Apparent Kd for binding of 4 patient-derived antidrug antibodies (BOIIB2, KM41, LE2E9, and BO2C11) to WT, C1918A,C1922A, and C2040A,C2188A FVIII protein. The data are from 3 independent experiments and bars and errors are mean ± SD. An ordinary 1-way analysis of variance was used to compare groups (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). Kd, dissociation constant.

Ablation of FVIII C1 and A3 disulfide bonds changes affinity for patient anti-FVIII drug antibodies. (A) Ribbon representation of the AlphaFold structure of human VIII lacking the unstructured B domain. The domains to which a panel of 4 patient-derived anti-FVIII drug antibodies bind (BOIIB2, KM41, LE2E9, and BO2C11) are shown. The residues that encompass the epitopes for the antibodies are shown as dots (see Table 1 for residue numbers) and the disulfide bond cysteines as yellow spheres. The red spheres are the cysteines that have been replaced with alanine. (B) Apparent Kd for binding of 4 patient-derived antidrug antibodies (BOIIB2, KM41, LE2E9, and BO2C11) to WT, C1918A,C1922A, and C2040A,C2188A FVIII protein. The data are from 3 independent experiments and bars and errors are mean ± SD. An ordinary 1-way analysis of variance was used to compare groups (∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). Kd, dissociation constant.

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