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Ikaika addresses excessive fibrosis deposition by introducing IKN-001, an antibody to protect a novel target: latent TGF-β binding protein (LTBP4), which modulates TGF-β, a master regulator of fibrosis.
LTBP4 is embedded in the extracellular matrix (ECM). The large latent complex comprise of LTBP4 bound to the small latent complex. The small latent complex includes TGF-β with its latency associated protein (LAP).
LTBP4 regulates the availability of latent TGF-β by sequestering TGF-β in its inactivated state, prohibiting TGF-β release and activation, and blocking its interaction with cell surface receptors.
Tissue injury and repair requires an orchestrated response that begins with locally activated proteases within injured tissues. These proteases cleave LTBP4’s hinge region, triggering release of latent TGF-β, a critical step in TGF-β activation.
Once active, TGF-β engages specific cell surface receptors, stimulating an intracellular cascade of signaling response and ultimately activation of profibrotic gene expression, which in turn promotes accumulation of matrix proteins.
Increased activation of TGF-β drives excess matrix formation, scarring within tissues, as well as muscle membrane disruption.
Ikaika has identified a novel anti-fibrotic target: IKN-001, a human antibody that protects LTBP4’s hinge region and blocks the first step in TGF-β activation. Ikaika’s first-in-class antibody, IKN-001, regulates the release of activated TGF-β by stabilizing the large latent complex.
Targeting LTBP4 is a novel therapeutic strategy to treat fibrotic disorders. This novel approach regulates TGF-β by restricting its activation and signaling in the target tissue, avoiding the consequences of systemic TGF-β inhibition.
Disease states like muscular dystrophy or other fibrotic disorders involve repetitive cell and tissue destruction, which results in TGF-β hyperactivation.
IKN-001 protects LTBP4’s hinge region, stabilizing the large latent complex and reducing active TGF-β.
IKN-001 maintains the integrity of the LTBP4 latent complex and promotes stabilization of inactive TGF-β. Inhibiting release of TGF-β reduces activation of downstream profibrotic gene expression, preventing excess matrix deposition and preserving organ function. Muscle cell membrane is also stabilized, and fibrosis onset is reduced.
Our team employed genomic tools, including genome-wide mapping and deep sequencing, to discover genetic regions that modified cardiac and skeletal muscle fibrosis. This approach identified multiple genetic regions that modified fibrosis and other aspects of cardiac and muscle degeneration. One of the strongest genetic signals was linked to the gene encoding latent TGF-β binding protein 4 (LTBP4). The subsequent genomic mapping studies were conducted in a mouse model of muscular dystrophy, a highly fibrotic disorder.
We determined that the hinge region of LTBP4, which is prone to cleavage, was distinctly different due to a genetic insertion/deletion between mice with high and low level of disease burden. Protective LTBP4 improved muscle cell stability and reduced scarring within the muscle tissue by reducing TGF-β release and activity. The human LTBP4 gene also has naturally occurring protective and deleterious forms which produce proteins associated with differential TGF-β activity, modifying disease progression in cardiac and skeletal muscle. These genetic studies identified LTBP4 as a key target for modifying fibrosis and established LTBP4’s mechanism of regulating TGF-β activation.
