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. 2022 May;33(5):918–935. doi: 10.1681/ASN.2021030372

Figure 5.

Figure 5.

A single injection of long-acting Fc-AK183 achieved week-long suppression of circulating IgA1 levels in humanized transgenic models of IgA1. (A) Through gene-targeting we created a transgenic mouse line with the replacement of the mouse IgA α chain locus with human α1 sequence (termed α1KI-Tg). The transgenic mice express hybrid IgA1 with human IgA1 heavy chain linked to mouse light chain. Heterozygous (WT/KI) mice were subjected to treatment with Fc-AK183 and changes in blood levels of humanized IgA1 were monitored by immunoblotting again human IgA1. The schematic showed the dynamics of IgA1 levels in response to treatment: before intervention (at regular serum level of IgA1), therapeutic Fc-AK183 degradation and clearance of IgA1, and continuous expression of the IgA1 transgene during the course of treatment. It should be noted that Fc-AK183 activity was expected to decline over time, and the therapeutic objective is to maintain low levels of blood IgA1 when the rate of clearance by Fc-AK183 is higher than endogenous production of IgA1 (between the two arrowheads). (B) The humanized mice (n=3) each received a single dose of 5 mg/kg body wt Fc-AK183. Postinjection blood draws were performed at 11 time points for up to 14 days (14d). (C) A representative example of a mouse treated with Fc-AK183 is shown with serum IgA1 levels by Western blotting (results of the other mice are in Supplemental Figure 4, and a separate cohort in Supplemental Figure 5). Within 0.05 hours after Fc-AK183 injection of the mouse, blood IgA1 in its intact form completely disappeared. The levels gradually reoccurred after 96 hours and only returned to its pretreatment level by 336 hours (14 days). In the meantime, mouse form of IgA remained stable because mouse IgA is not a substrate of AK183. (D) A summary of endogenous human IgA1 levels in response to Fc-AK183 treatment showed a U-shaped curve, with total suppression of blood IgA1 levels between 2 and 96 hours. (E) Body weight of mice (n=3) receiving Fc-AK183 injection did not show a decline during post-treatment days.