DNA-targeting antibodies may be therapeutic options for AAV
A pair of deoxymabs could attack inflammation but not immune system
Patrys’ PAT-DX1 and PAT-DX3, two DNA-targeting antibodies known as deoxymabs, can suppress production of the antimicrobial webs implicated in ANCA-associated vasculitis (AAV) without weakening other immune responses, according to preclinical work.
These webs, called neutrophil extracellular traps (NETs), are made up of a scaffold of DNA and enzymes that catches and promotes the destruction of harmful microbes to protect the body from infection. When these webs are left down for too long, however, they may contribute to autoimmune diseases like AAV.
The data also showed that these deoxymabs were able to reduce inflammation and kidney damage in a mouse model of AAV-related glomerulonephritis, a condition marked by inflammation of the kidney’s filtering units.
The results suggest “there may be opportunities to develop deoxymabs as a therapeutic for ANCA vasculitis, and potentially for other related autoimmune diseases,” James Campbell, PhD, CEO, and managing director at Patrys, said in a company press release.
Presentation findings
These preclinical findings were shared by Kim O’Sullivan, PhD, an immunologist at Monash University in Melbourne, Australia, in an oral presentation at the 21st International Vasculitis Workshop, which ended today, April 10, in Barcelona, Spain.
The presentation was titled “DNA repair antibody Deoxy Mab 1 inhibits neutrophil extracellular traps (NETs) and attenuates inflammation and kidney injury in experimental anti neutrophil cytoplasmic antibody vasculitis” (O-007).
“We are pleased to present these important discoveries at the leading global meeting on vasculitis,” O’Sullivan said. “We are particularly excited by the discovery that both PAT-DX1 and PAT-DX3 are able to reduce symptoms of inflammation without negatively impacting the immune system as this [blood vessel inflammation] is one of the major side-effects of existing therapies for vasculitis.”
AAV, or ANCA vasculitis, occurs when self-reactive antibodies, called ANCAs, wrongly target neutrophils, a type of immune cell. The targeting causes these cells to launch an inflammatory response that damages small, vulnerable blood vessels, leading to symptoms in the kidneys and other organs in the body.
Neutrophils can cast weblike structures called NETs, which they use to prevent harmful microbes from spreading and causing infection. Among the many enzymes found in NETs are proteinase 3 and myeloperoxidase (MPO), the most common targets of AAV-driving ANCAs.
In AAV, neutrophils are overactive and overproduce NETs, which are thought to drive autoimmunity by revealing these targets to the immune system, triggering a constant loop of inflammation and damage in small blood vessels.
PAT-DX1 and PAT-DX3 are deoxymabs derived from 3E10, a DNA-targeting antibody that was first identified in a mouse model of the most common form of lupus, another autoimmune disease.
Deoxymabs are known to enter cells, bind to DNA, and suppress the cell’s DNA damage repair process (DDR), which is known to contribute to DNA release as a mechanism of NET formation.
Earlier work showed that PAT-DX1, a fragment of the original 3E10, can suppress DNA release from cancer cells. Compared with a placebo, it also reduced the area occupied by NETs cast by lab-grown neutrophils isolated from a mouse model of inflammation. PAT-DX3 is a full-size antibody expected to have similar effects.
O’Sullivan and her team then tested PAT-DX1 and PAT-DX3 for their potential to block NET formation and reduce damaging inflammation in the small blood vessels in the kidneys in preclinical models.
Both deoxymabs were found to reduce the formation of NETs by lab-grown human neutrophils. However, they had no effect on the cells’ phagocytosis, whereby neutrophils surround and destroy unwanted material, including microbes; the cells’ survival; or the cells’ release of extra MPO or elastase, another component of NETs.
These findings suggest these antibodies may leave neutrophils’ normal immune response unharmed.
In a mouse model of glomerulonephritis caused by MPO-related AAV, both PAT-DX1 and PAT-DX3 significantly reduced NET formation, MPO deposition, inflammation, and kidney damage. At least for PAT-DX1, this reduction may have occurred because of the reduction in the number of immune cells that wrongly reacted to MPO as if it were a threat.
“Therapeutic targeting of NETs with [PAT-DX1] in the experimental model reduced inflammation and kidney injury suggesting it may be of potential benefit as treatment for AAV,” the team wrote in the abstract.
“ANCA vasculitis is a challenging condition and, while current treatments have transformed it into a relapsing/remitting disease, they are associated with increased drug-related toxicities and organ damage,” Campbell said. “In view of this, we believe a therapeutic that is able to reduce the inflammation associated with this disease without suppressing the immune system could provide a very attractive therapeutic option for patients.”
Patrys is scaling up the production of a clinical-grade PAT-DX1 product that meets Good Manufacturing Practice (GMP) standards for quality, with the aim of initiating first-in-human clinical testing this year.
“It is particularly exciting to see the potential opportunities to develop or partner our deoxymab technology expand while our GMP manufacturing of PAT-DX1 is underway and nearing completion,” Campbell said.
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