Resolution of fibrosis is a high unmet medical need
Fibrosis, a pathological process caused by over-deposition of collagen in the extracellular space, can affect virtually any organ. Fibrosis is typically initiated by an inciting injury caused by traumatic, inflammatory, infectious, metabolic, hemodynamic or autoimmune mechanisms. Tissue damage triggers a complex cascade of biological events that involves multiple cell types and culminates in collagen secretion by effector cells. This process represents a physiologic response to cell injury in the short term, but becomes pathologic when it does not resolve over time, leading to tissue fibrosis and loss of organ functionality. While there are some therapies that slow down the progression of fibrosis, so far there is none that actually reverses fibrosis and that restores the physiological function of a fibrotic organ.
HGF: Master and Commander of the cellular anti-fibrotic program
Hepatocyte Growth Factor (HGF) is a pleiotropic cytokine of mesenchymal origin that mediates a unique biological program resulting from the fine orchestration of a wide array of biological activities, including cell proliferation, survival, motility and differentiation. The high affinity receptor for HGF, the MET tyrosine kinase, is expressed mainly by epithelial and endothelial cells, but also by other cell types (e.g. muscle, neuronal, hemopoietic). Notably, the majority of myofibroblasts, the cells responsible for collagen over-deposition in a fibrotic tissue, also express MET. HGF can have different activity on distinct cell types. On one hand, it stimulates epithelial and endothelial cells to proliferate, migrate and survive; on the other, it inhibits collagen synthesis and causes myofibroblast cell death.
HGF is essential for embryo development, during which it drives stem cell proliferation, migration and survival. In the adult, HGF masters wound healing and tissue regeneration, promoting the reconstruction of the damaged epithelium, restoring a functional vasculature, and curbing the proliferation of myofibroblasts, thus resolving the inciting injury and preventing hyper-deposition of collagen. Remarkably, HGF induces epithelial cells to secrete proteases that digest collagen and stimulates them to invade the digested extracellular matrix. This process leads the newly regenerated healthy tissue to reconquer the space that was previously occupied by fibrotic matrix, thus resolving fibrosis.
Pharmacological and biochemical limitations challenge translation of HGF into the clinic
Overwhelming experimental evidence generated in three decades of scientific research indicates that HGF displays potent healing and curative effect in a variety of preclinical models of fibrotic, inflammatory, autoimmune and degenerative diseases. While the therapeutic potential of HGF has been recognized since its discovery in the 90’s, translation of HGF to the clinic has been challenging. In fact, HGF has a very short half-life in circulation; it has high avidity for extracellular matrix components, rendering systemic administration in patients problematic; its manufacture is complex and expensive, making it difficult to produce clinical grade HGF cost-effectively; finally, protein instability jeopardizes the storage of large factor stocks for clinical and commercial supply.
HGF-mimetic “agomAbs” combine the powerful therapeutic potential of HGF with the excellent drug-like properties of antibodies
To overcome the pharmacological limitations of HGF, AgomAb has generated a set of agonistic monoclonal antibodies (“agomAbs”) directed against the MET receptor. These antibodies bind with high affinity to MET and promote receptor dimerization and activation, resembling the molecular action of HGF.
While MET-agonistic agomAbs maintain the full therapeutic potential of HGF from a biological viewpoint, they display the excellent drug-like properties of antibodies, including enhanced stability, a high specificity/low toxicity profile, facilitated biodistribution, and the possibility to tune effector functions by protein engineering. Furthermore, the industrial manufacturing of clinical grade antibodies follows established procedures, ensuring high yields and a long shelf life. Most importantly, the clinical use of antibodies has been –and continues to be– validated in thousands of patients in a multitude of indications.
Our HGF-mimetic agomAbs have been designed and selected such that full cross-reactivity with human, non-human primate and rodent MET is maintained. Not only do agomAbs cross-react, they also display the very same powerful biological activity in all the corresponding species-specific cell systems. Cross-species equivalency allows thorough characterization of the selected leads for efficacy and safety in animal models prior to the initiation of clinical trials.