Calluna Pharma is developing CAL101, a first-in-class humanized IgG4 monoclonal antibody that neutralizes S100A4, the upstream amplifier that locks fibroblasts and macrophages into the self-sustaining loop behind idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis is a progressive, fatal scarring disease with no cure. It begins with injury to the alveolar epithelium and becomes a dysregulated repair response that amplifies itself.
Injured or stressed cells release the calcium-binding protein S100A4 into the extracellular space.
S100A4 drives activated fibroblasts to release pro-fibrotic proteins such as collagen. Activated macrophages release more S100A4. The two cell types hold each other in a self-sustaining amplification loop.
Collagen accumulates into scar tissue, and the fibrotic response continues even after the initiating injury is no longer present.
Therapies that broadly suppress fibroblast activity may also affect normal physiological functions, including other cell types in other organs, which limits tolerability. Therapies that target downstream pathways can be constrained by parallel or compensatory pathways, because fibrotic signaling is networked and redundant. Position in the cascade determines what is therapeutically possible.
The sequence the animation shows, in order. CAL101 acts at a single upstream step; everything downstream follows from that.
Alveolar epithelial injury triggers a dysregulated wound-healing response.
Stressed and injured cells release S100A4 into the extracellular space.
S100A4 activates fibroblasts and macrophages. Fibroblasts release collagen; macrophages release more S100A4. The loop sustains itself.
CAL101, a humanized IgG4 monoclonal antibody, binds extracellular S100A4 before it reaches its receptors.
Deprived of the upstream amplifying signal, excessive fibrotic and inflammatory signaling is dampened at an early extracellular step.
The downstream pathways are not shut down. They are deprived of an upstream disease amplifying signal that was driving them beyond their normal function.
Upstream targeting in fibrosis has historically carried toxicity when the target is non-specific. S100A4 is different. Extracellular S100A4 is associated with stress and tissue injury, so it is active primarily in disease, not in normal cellular maintenance. Neutralizing it dampens the amplifier without touching the physiological pathways the body still needs.
CAL101 has completed Phase 1 and is in a randomized, placebo-controlled Phase 2 study in IPF.
CAL101 in IPF is the lead. The same upstream-amplifier logic extends to a discovery-stage program against oxidized phospholipids.
| Program | Target | Indication | Stage | Status |
|---|---|---|---|---|
| CAL101 | S100A4 | Idiopathic pulmonary fibrosis | Phase 2 | AURORA (NCT06736990) enrollment complete · topline Q1 2027 · FDA Orphan Drug Designation |
| CAL103 | OxPL | Chronic inflammatory indications | Discovery | Preclinical |
A randomized, double-blind, placebo-controlled Phase 2 study of CAL101 in patients with IPF. Participants are randomized 60:40 to CAL101 or placebo, receive monthly intravenous infusions for approximately six months, and may continue their current IPF treatment. Primary endpoint: change from baseline in forced vital capacity (FVC). ClinicalTrials.gov NCT06736990.
S100A4 sits above the redundant fibrotic network. Neutralizing it dampens multiple pathways from a single point.
Extracellular S100A4 is a signal of stress and injury, which is what makes upstream targeting tolerable.
CAL101 aims to change the treatment approach for IPF and potentially a broad range of fibrotic and inflammatory disorders.
CAL101 is investigational and has not been approved by the FDA or other regulatory authorities.
Interested in CAL101, the AURORA study, or partnership opportunities in fibrotic and inflammatory disease? Calluna would welcome the conversation.
Contact Calluna