9RRW
Anti FIXa VHH of inno8 in complex with truncated FIXa (catalytic and EGF2 domains)
Summary for 9RRW
| Entry DOI | 10.2210/pdb9rrw/pdb |
| Descriptor | Coagulation factor IX, Factor IXa binding VHH of inno8, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | vhh, factor ix, factor viiia mimetic, inno8, blood clotting |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 95759.01 |
| Authors | |
| Primary citation | Lund, J.,Bjelke, J.R.,Granata, D.,Egebjerg, T.,Bardonnet, P.L.,Wang Zhuoran, Z.,Johansson, E.,Rask Poulsen, B.,Dahl Nissen, J.B.,Sassene, P.J.,Franklin Nielsen, P.,Jorgensen, L.,Bjelke, M.,Chen Sr., P.,Bloem, E.,Loftager, M.,Lamberth, K.,Kopp, K.L.,Demuth, H.,Wahlund, P.O.,Mandal Mortensen, M.,Nissen, B.,Pedersen, M.D.,Balantic-Nielsen, E.,Monrad Grandal, M.,Westall, A.,Vegge, A. Development of Inno8, an orally administered factor VIIIa-mimetic antibody fragment for treatment of hemophilia A. Blood, 2026 Cited by PubMed Abstract: Hemophilia A (HA) is caused by factor VIII (FVIII) deficiency and requires lifelong prophylaxis. Although activated FVIII (FVIIIa)-mimetic antibodies have enabled subcutaneous administration, thereby reducing treatment burden compared with intravenous FVIII replacement, an oral therapy remains a significant unmet need for individuals with HA. Here, we describe Inno8, a novel bispecific single-chain antibody fragment comprising two variable domains of heavy-chain antibodies that bridges coagulation factors IXa and X to mimic FVIIIa function and is engineered for oral delivery. Inno8 was generated from llama and alpaca immunizations and optimized through iterative structure-guided and machine learning-assisted engineering to enhance FVIIIa-mimetic activity, reduce the isoelectric point (pI) to improve oral bioavailability, and extend systemic exposure through site-specific fatty acid conjugation. Formulations containing permeation enhancer SNAC and solubilizing agent niacinamide were evaluated in preclinical models. Procoagulant activity was assessed in HA plasma and whole blood using thrombin generation assays and thromboelastography. Inno8 demonstrated, on average, 90‑fold greater in vitro potency than a sequence‑identical emicizumab analogue. Reducing the pI increased oral exposure ~10-fold in rats, and a tablet formulation containing SNAC and niacinamide demonstrated significant oral bioavailability (0.215% with 4-hour post dose fasting) and a 115-hour half-life in beagle dogs. Together, these findings support Inno8 as a potent, orally deliverable FVIIIa-mimetic and provide a framework for engineering oral, long-acting antibody-based therapies. Inno8 is currently in clinical evaluation, with first-in-human dosing completed (VOYAGER1, NCT06649630). Pending further clinical evaluation, Inno8 may represent an advance in biologics development and a potential non-invasive prophylactic therapy for individuals with HA. PubMed: 42784525DOI: 10.1182/blood.2026034676 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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