Detailed epitope mapping of neutralizing anti-drug antibodies against recombinant α-galactosidase A in patients with Fabry disease

Scharnetzki, David; Stappers, Franciska; Lenders, Malte; Brand, Eva

doi:10.1016/j.ymgme.2020.08.005

Cited by 7 publications

(6 citation statements)

References 20 publications

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“…Previous reports demonstrated a significant variation of antibody epitopes against AGAL. [12,18] Therefore, patients' samples with known ADA epitopes were used [18] to ensure that the reference antibody represents a wide spectrum of antibody epitopes against AGAL.…”

Section: Patients' Samplesmentioning

confidence: 99%

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Generation and Characterization of a Polyclonal Human Reference Antibody to Measure Anti-Drug Antibody Titers in Patients with Fabry Disease

Lenders¹,

Scharnetzki²,

Heidari³

et al. 2021

IJMS

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Male patients with Fabry disease (FD) are at high risk for the formation of antibodies to recombinant α-galactosidase A (AGAL), used for enzyme replacement therapy. Due to the rapid disease progression, the identification of patients at risk is highly warranted. However, currently suitable references and standardized protocols for anti-drug antibodies (ADA) determination do not exist. Here we generate a comprehensive patient-derived antibody mixture as a reference, allowing ELISA-based quantification of antibody titers from individual blood samples. Serum samples of 22 male patients with FD and ADAs against AGAL were pooled and purified by immune adsorption. ADA-affinities against agalsidase-α, agalsidase-β and Moss-AGAL were measured by quartz crystal microbalance with dissipation monitoring (QCM-D). AGAL-specific immune adsorption generated a polyclonal ADA mixture showing a concentration-dependent binding and inhibition of AGAL. Titers in raw sera and from purified total IgGs (r2 = 0.9063 and r2 = 0.8952, both p < 0.0001) correlated with the individual inhibitory capacities of ADAs. QCM-D measurements demonstrated comparable affinities of the reference antibody for agalsidase-α, agalsidase-β and Moss-AGAL (KD: 1.94 ± 0.11 µM, 2.46 ± 0.21 µM, and 1.33 ± 0.09 µM, respectively). The reference antibody allows the ELISA-based ADA titer determination and quantification of absolute concentrations. Furthermore, ADAs from patients with FD have comparable affinities to agalsidase-α, agalsidase-β and Moss-AGAL.

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Section: Patients' Samplesmentioning

confidence: 99%

“…To exclude a non-specific binding of the reference antibody, individual ELISAs with 100 ng per well of agalsidase-α, BSA, a negative control peptide (sequence: HWYITTG-PVREK) [12,18], and a non-homologous AGAL from Aspergillus niger [19] were performed.…”

Section: Elisa-based Measurement Of Agal-binding Iggsmentioning

confidence: 99%

Generation and Characterization of a Polyclonal Human Reference Antibody to Measure Anti-Drug Antibody Titers in Patients with Fabry Disease

Lenders¹,

Scharnetzki²,

Heidari³

et al. 2021

IJMS

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“…Due to the complexity, such an approach would not be feasible for measuring comparable characteristics for human polyclonal antibodies. Instead, epitope mappings with fragmented AGAL successfully revealed individual epitopes for patients, suggesting polyclonal antibodies [63].…”

Section: Methods For Determination Of Adasmentioning

confidence: 99%

“…2g). Since ADAs in affected patients with FD are polyclonal and thus recognize different epitopes [7,63], it can be assumed that in most individuals a combination of the mechanisms leads to decreased therapeutic efficacy.…”

Section: Biochemical Impact Of Neutralizing Adasmentioning

confidence: 99%

Mechanisms of Neutralizing Anti-drug Antibody Formation and Clinical Relevance on Therapeutic Efficacy of Enzyme Replacement Therapies in Fabry Disease

Lenders

Brand

2021

Drugs

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“…In a retrospective study, total cholesterol and HDL levels were measured before ERT and 10 years after ERT (Stepien and Hendriksz, 2017). Patients who underwent ERT displayed higher HDL levels than those who did not, and ERT was found to (Scharnetzki et al, 2020) exert a cardioprotective effect. These studies indicate that targeting cholesterol metabolism may be a feasible therapeutic option for Fabry disease.…”

Section: Lipid Metabolismmentioning

confidence: 99%

Fabry disease: Mechanism and therapeutics strategies

Ren

Zhang

et al. 2022

Front. Pharmacol.

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Fabry disease is a monogenic disease characterized by a deficiency or loss of the α-galactosidase A (GLA). The resulting impairment in lysosomal GLA enzymatic activity leads to the pathogenic accumulation of enzymatic substrate and, consequently, the progressive appearance of clinical symptoms in target organs, including the heart, kidney, and brain. However, the mechanisms involved in Fabry disease-mediated organ damage are largely ambiguous and poorly understood, which hinders the development of therapeutic strategies for the treatment of this disorder. Although currently available clinical approaches have shown some efficiency in the treatment of Fabry disease, they all exhibit limitations that need to be overcome. In this review, we first introduce current mechanistic knowledge of Fabry disease and discuss potential therapeutic strategies for its treatment. We then systemically summarize and discuss advances in research on therapeutic approaches, including enzyme replacement therapy (ERT), gene therapy, and chaperone therapy, as well as strategies targeting subcellular compartments, such as lysosomes, the endoplasmic reticulum, and the nucleus. Finally, the future development of potential therapeutic strategies is discussed based on the results of mechanistic studies and the limitations associated with these therapeutic approaches.

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Detailed epitope mapping of neutralizing anti-drug antibodies against recombinant α-galactosidase A in patients with Fabry disease

Cited by 7 publications

References 20 publications

Generation and Characterization of a Polyclonal Human Reference Antibody to Measure Anti-Drug Antibody Titers in Patients with Fabry Disease

Generation and Characterization of a Polyclonal Human Reference Antibody to Measure Anti-Drug Antibody Titers in Patients with Fabry Disease

Mechanisms of Neutralizing Anti-drug Antibody Formation and Clinical Relevance on Therapeutic Efficacy of Enzyme Replacement Therapies in Fabry Disease

Fabry disease: Mechanism and therapeutics strategies

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