Edimer

EDI200 is a recombinant protein being developed by Edimer as a treatment for certain patients with X-linked Hypohidrotic Ectodermal Dysplasia (XLHED).

Ectodysplasin-A1 (EDA-A1) is a type II transmembrane protein and member of the TNF family. The proteolytic processing of EDA-A1 releases a soluble ligand, which binds to its cognate receptor EDAR, inducing an intracellular pathway leading to the development of ectodermal appendages during embryogenesis. EDAR signals via the adapter molecule EDAR-ADD and subsequently activates intracellular NFκB. This signaling is believed to regulate transcription of target genes that form various ectodermal appendages (including skin and teeth).

The laboratories of Prof. J. Tschopp and Prof. P. Schneider (University of Lausanne, Switzerland) discovered a remarkable feature shared by many of the ligands of the TNF family. Their work showed that the TNF domain of these ligands constitutes homotrimers, which are still capable of binding to their corresponding receptors, while they no longer trigger intracellular signaling. It is only when these homotrimers are multimerized, that an intracellular signaling cascade is elicited.

Multimerization was successfully obtained using cross-linking antibodies or by genetic modification of the TNF domain of the ligand with a multimerizing domain. EDI200 (or Fc-EDA1) was engineered as a fusion protein between the Fc domain of human immunoglobulin G1 (IgG1) and the TNF domain of human EDA-A1.

The rationale for the use of the Fc moiety is threefold: 1. It substitutes for the collagen domain of EDA-A
1 – which acts as a multimerization domain – the protein is therefore sufficiently oligomerlzed to trigger receptor signaling.
2. The Fc moiety contributes to the stability of the molecule in vivo and
3. It ensures delivery of the protein from the maternal blood to the embryo through Fc receptor mediated transplacental transport should pre-natal delivery be required.

EDI200 has been shown to bind EDAR and induce the activation of NFκB and has been successfully tested in two animal models as a replacement therapy in conditions where the naturally produced EDA-A1 molecule is missing. EDI200 is made in CHO cells stably producing the protein, cultured in serum and protein free medium. EDI200 is translated within the cells as a 395 amino acid protein, which is cleaved and secreted as a 380 amino acid protein. EDI200 is purified by standard chromatographic methods.

Figure 1 – Organization of EDI200 as a Hexamer

The rationale for the use of EDI200 in XLHED patients is based on the lack of functional EDA-A1 protein in these patients – which during development affects the formation of ectodermal structures. EDI200 substitutes for this protein during development (see Figure2).

Figure 2 - Rationale

The Tabby phenotype in mice is similarly a result of EDA-A1 deficiency. The initial proof of concept in vivo for the use of EDI200 in XLHED was performed in the Tabby mouse model of XLHED. Treatment of pregnant mice with EDI200 permanently rescued the Tabby phenotype of the offspring. Equivalent results were achieved after injecting the protein into Tabby mice shortly after birth.

In addition dogs carrying the EDA mutation exhibit a phenotype equivalent to that of humans with XLHED – EDI200 has been used to successfully correct the pheonotype when administered shortly after birth in these dogs (materno-fetal immunoglobulin transport is specifically inhibited in the dog, therefore all data generated to date in the dog has been achieved with post-natal administration of EDI200).

For further information in the research supporting EDI200 please review the key research articles listed here.