Abstract: TH-PO0840
ErbB Ligand Selectivity and Preclinical Pharmacokinetics of DTR8, a Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF) Antagonist for Crescentic Glomerulonephritis
Session Information
- Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1900 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Pichard, Sylvain, Université Paris-Saclay, CEA, INRAE, DMTS, SIMoS, Gif sur Yvette, France
- Fernandes Reis, Cátia, DETERA Therapeutics, Paris, France
- Cantais Marzullo, Margaux, Université Paris-Saclay, CEA, INRAE, DMTS, SIMoS, Gif sur Yvette, France
- Seidakhanova, Aruzhan, Université Paris-Saclay, CEA, INRAE, DMTS, SIMoS, Gif sur Yvette, France
- Barbe, Peggy, Université Paris-Saclay, CEA, INRAE, DMTS, SIMoS, Gif sur Yvette, France
- Keck, Mathilde, Université Paris-Saclay, CEA, INRAE, DMTS, SIMoS, Gif sur Yvette, France
- Lécuelle, Benoît, Ecole Nationale Veterinaire d'Alfort, Maisons-Alfort, Île-de-France, France
- Theodoro, Frederic, Université Paris-Saclay, CEA, INRAE, DMTS,SPI, Gif sur Yvette, France
- Anvi Laetitia, Nguyen, Université Paris-Saclay, CEA, INRAE, DMTS,SPI, Gif sur Yvette, France
- Castelli, Florence A., Université Paris-Saclay, CEA, INRAE, DMTS,SPI, Gif sur Yvette, France
- Pruvost, Alain, Université Paris-Saclay, CEA, INRAE, DMTS,SPI, Gif sur Yvette, France
- Tharaux, Pierre-Louis, INSERM, PARCC, Paris, France
- Gillet, Daniel, Université Paris-Saclay, CEA, INRAE, DMTS, SIMoS, Gif sur Yvette, France
Background
HB-EGF is a key mediator of EGFR/ErbB signaling in crescentic glomerulonephritis (CGN). In CGN, glomerular injury induces HB-EGF expression in podocytes and parietal epithelial cells, promoting EGFR activation, dedifferentiation, proliferation and crescent formation. We previously showed that DTR8 protects glomerular architecture in an accelerated anti-GBM porcine model of CGN. Here, we evaluated DTR8 selectivity across ErbB1/ErbB4 ligands and its pharmacokinetics.
Methods
DTR8 was engineered from the diphtheria toxin receptor-binding domain to antagonize human HB-EGF with picomolar affinity, improved solubility and reduced immunogenicity/antigenicity. Selectivity was assessed in proliferation assays using EGF, TGF-α, amphiregulin, epiregulin, betacellulin, epigen, HB-EGF and neuregulins. Pharmacokinetics were characterized after intravenous and extravascular administration in mouse and pig.
Results
DTR8 potently inhibited HB-EGF-driven proliferation, achieving complete suppression, but showed no significant inhibition of most other ErbB1/ErbB4 ligands. Among EGFR ligands, only amphiregulin showed measurable inhibition, with approximately 100-fold lower potency than HB-EGF. At high DTR8 concentration, amphiregulin-driven proliferation was partially reduced, whereas responses to other EGFR ligands were preserved. Pharmacokinetic analyses showed a short intrinsic half-life after intravenous administration, whereas extravascular dosing showed absorption-limited kinetics with prolonged exposure. Bioavailability was approximately 30% after subcutaneous administration in mice and 22% after intramuscular administration in pigs. DTR8 remained stable for at least 2 h in whole blood and plasma from four animal species and humans, and was detectable in urine.
Conclusion
DTR8 combines high-affinity HB-EGF antagonism, ErbB ligand selectivity and pharmacokinetics compatible with extravascular administration, including subcutaneous dosing. These data are consistent with its efficacy in a porcine CGN model. Limited amphiregulin cross-reactivity may be beneficial, given its role in myeloid-cell recruitment in CGN. DTR8 supports targeted inhibition of disease-driving HB-EGF signaling while limiting broad ErbB pathway blockade.
Acknowledgment
We thank François Becher for LC-MS/MS DTR8 dosage method.
Funding
- Government Support – Non-U.S.