Why target growth factor pathways for fibrotic indications?
Fibrotic processes are the underlying factors in a variety of difficult-to-treat diseases, resulting in progressive organ failure. For most fibrotic diseases, blocking inflammatory events only, e.g. by inhibiting cytokine signaling, is not expected to deliver substantial disease stabilization or reversal. Because inflammation and fibrosis are such complex and interconnected processes, one needs to identify assets with broad mode of actions able to address redundancy across multiple pathways.
Growth factor pathways have evolved to coordinate broad morphogenic and tissue repair programs, and can be leveraged to profoundly alleviate tissue injury, fibrotic remodeling, and organ failure. Because growth factors possess such broad activity, it is important to have a deep understanding about how to modulate them, and how to devise small molecules or biologics to do this.
This is where we leverage our deep understanding of growth factor biology and employ smart small molecules targeting the TGFβ pathway and agonistic antibodies targeting the HGF/MET pathway. The company’s pipeline consists of unique assets with a novel mode of actions against well-validated and potentially disease modifying targets with the aim to repair tissue injury, resolve fibrosis and restore organ function in patients with high unmet medical need.
“The TGF-ẞ pathway plays a key role in fibrosis. Our specifically engineered compounds allow localized targeting of ALK-5 while avoiding systemic side effects. An organ-restricted approach could be the key to unlocking treatment options for a range of diseases.”
Ramon Bosser, Head of Agomab Spain Operations
Why are we targeting the TGF-ẞ pathway?
TGF-ß is a core regulator of fibrogenic pathways and is considered the major driver of fibrosis. Once activated, TGF-ß coordinates the conversion of quiescent fibroblasts into myofibroblasts in addition to initiating the direct transcription of pro-fibrotic genes.
Inhibition of the intracellular kinase domain of the TGF-ß receptor (ALK-5) is desirable in the treatment of fibrotic disorders for its potential in blocking canonical and non-canonical TGF-ß signaling. Though several TGF-ß inhibitor approaches have been stalled by systemic toxicity levels, specific ALK-5 inhibitors have shown strong anti-fibrotic effects in the gastrointestinal tract, lungs, and liver.
Armed with this knowledge, we are creating organ-restricted ALK-5 inhibitors to leverage blockade of the TGF-ß pathway while avoiding systemic exposure.
“New insights into molecular pathways and targets that master tissue regeneration, such as the HGF/MET axis, together with the robustness and specificity of monoclonal antibodies, will create a new level of therapeutic potential for a variety of chronic and acute diseases.”
Paolo Michieli, Chief Scientific Officer
Why are we targeting the HGF/MET pathway?
HGF is a pleiotropic growth factor of mesenchymal origin that mediates a variety of biological processes, including cell proliferation, cell survival, cell motility and cell differentiation. The high affinity receptor for HGF is the tyrosine kinase MET. This receptor is mainly expressed by epithelial and endothelial cells but can also be found in other cell types such as muscle, neuronal and hematopoietic cells as well as in the majority of myofibroblasts.
While the therapeutic and regenerative potential of HGF has been recognized since its discovery in the 1990s, translation of this growth factor to the clinic has been challenging, mainly due to its short plasma half-life as well as the difficulty to manufacture clinical-grade molecules cost-effectively.
Benefitting from argenx’s validated SIMPLE antibodyTM technology platform, we have created a set of full and partial MET-agonistic antibodies, allowing us to achieve the desired activation of the HGF/MET pathway in patients.
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