The serine protease HTRA1 has multiple targets, including extracellular matrix proteins such as fibronectin. Fibronectin fragments generated by HTRA1 further induce synoviocytes to upregulate the production of MMP1 and MMP3. By acting on TGF-β signaling, HTRA1 regulates numerous physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, it degrades TSC2, leading to the activation of TSC2 downstream targets.
Expression distribution of HTRA1
HTRA1 is mainly expressed in mesothelial cells, Müller cells, fibroblasts, and ovarian stromal cells, and is also expressed to a lesser extent in immune cells such as macrophages, Hofbauer cells, Kupffer cells, Langerhans cells, and erythroid cells.
(Data source: Uniprot)
Structure of HTRA1
HTRA1 is a secreted protein composed of 480 amino acids. HTRA1 is a homo-oligomeric protein that typically functions as a trimer. This is one of its most striking structural features. Each monomer contains multiple domains that coordinate its protease activity and substrate interactions. The HTRA1 monomer primarily includes the insulin-like growth factor binding protein domain (IGFBP-domain), the Kazal-type serine protease inhibitor domain (KAZAL-domain), the trypsin-like serine protease domain (TRYSP-domain), and the PDZ domain.
The active form of HTRA1 is a homotrimer, in which three monomers are bound to each other through their PDZ domains and protease domains, forming a structure resembling a three-bladed propeller.
(Data source: Truebestein L, et al. Nat Struct Mol Biol. 2011)
Regulation of HTRA1 in the tumor microenvironment
HTRA1 activates the basic fibroblast growth factor (bFGF)/fibroblast growth factor 2 (FGF2) signaling axis secreted by gastric cancer cells by activating the nuclear factor κB (NF-κB) signaling pathway, promoting the transdifferentiation of normal fibroblasts into cancer-associated fibroblasts (CAFs); in vascular endothelial cells, HTRA1 affects angiogenesis through the Notch signaling pathway.
(Data source: Song S, et al. Int J Gen Med. 2024)
HTRA1-targeted therapy
Galegenimab (FHTR2163) is a fragment antigen-binding (Fab) humanized monoclonal antibody targeting the trimerized HtrA1 protein. Galegenimab inhibits the HtrA1 protease by forming a macromolecular complex with HtrA1 and binding three independent anti-HtrA1 Fabs to each trimer subunit. It is being developed by Roche for the treatment of genetic disorders, malformations, and ocular diseases.
NCT03972709 is a study evaluating the safety, tolerability, and efficacy of galegenimab in patients with geographic atrophy secondary to age-related macular degeneration (AMD) (GALLEGO). The study found no statistically significant difference between the treatment and sham groups. However, the incidence of intraocular inflammation was high in treated patients (7.1%, 16 of 224 patients). The DMC recommended early termination of the study based on an early benefit/risk analysis.
(Data source: clinicaltrials)
