A bispecific antibody targeting Gd-IgA1 and TfR1 enhances Gd-IgA1 degradation and mitigates IgA nephropathy

 

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A bispecific antibody targeting Gd-IgA1 and TfR1 enhances Gd-IgA1 degradation and mitigates IgA nephropathy

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Mengting
Fang
Mengting Fang fang70320@163.com Guangdong Provincial People’s Hospital Department of Nephrology guangzhou China *
Xueqing Yu yuxueqing@gdph.org.cn Guangdong Provincial People’s Hospital Department of Nephrology guangzhou China -
 
 
 
 
 
 
 
 
 
 
 
 
 

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by glomerular mesangial deposition of IgA1 immune complexes. Galactose-deficient IgA1 (Gd-IgA1) is a key pathogenic driver of the disease. Reducing its levels represents a promising therapeutic strategy.

Here, we leverage the rapid endocytic recycling of transferrin receptor 1 (TfR1) to design a bispecific antibody that co-binding Gd-IgA1 and TfR1. This approach aims to redirect Gd-IgA1 into the lysosomal degradation pathway via TfR1-mediated internalization.

We isolated an anti-Gd-IgA1 antibody using phage display and engineered it into a TfR1-targeting bispecific antibody. Biolayer interferometry confirmed dual binding specificity. Cellular assays demonstrated efficient internalization of the bispecific antibody, with colocalization observed in early, late, and recycling endosomes marked by Rab5, Rab7, and Rab11.

Our study establishes TfR1 as an effective membrane protein for targeted degradation of pathogenic Gd-IgA1 and highlights the therapeutic potential of this bispecific antibody platform for the treatment of IgAN.

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