323. Imlifidase in ANCA associated Vasculitis
Creators: name: Janis Sonnemann1, 2
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background/ Objectives: </strong>ANCA are IgG directed against the neutrophil antigens myeloperoxidase (MPO) and proteinase 3 (PR3). Through binding and activation of neutrophils they cause severe and irreversible tissue damage. A common and life-threatening manifestation is pulmonary capillaritis presenting as diffuse alveolar hemorrhage (DAH). After PEXIVAS failed to prove significant benefits of plasma exchange (PE) clinicians are left with supportive care and unspecific immunosuppressive regimens which require on average 90 days to induce remission. Imlifidase is an IgG-degrading enzyme derived from Streptococcus pyogenes which rapidly cleaves human IgG into F(ab’)2 and Fc fragments. We report on the first use of imlifidase in a 35-year-old male patient with severe refractory DAH due to PR3-ANCA positive granulomatosis with polyangiitis and studied ANCA dynamics and in-vitro effects. <strong>Methods:</strong> The patient was treated intravenously with 20 mg of imlifidase. Clinical characteristics were followed closely, ANCA titer dynamics were monitored daily. Inhibitory effect of imlifidase was measured in-vitro. Tumor necrosis factor-α (TNFα)-primed isolated polymorphonuclear leukocytes were stimulated with monoclonal antibody (mAb) against MPO or PR3. Sera were pretreated with either imlifidase or control (ctrl) buffer. Generation of reactive oxygen species (ROS) was measured using superoxide dismutase inhibitable ferricytochrome c reduction. <strong>Results</strong>: Hours after administration of imlifidase hemoptysis ceased and lung function improved significantly, enabling rapid weaning from extra-corporal membrane oxygenation (ECMO). This coincided with rapid ANCA seroconversion (Fig. 1A). In-vitro treatment with imlifidase effectively inhibited ANCA-mediated neutrophil activation (Fig. 1B). Unfortunately, the patient succumbed to sepsis after colonic bleeding 26 days after treatment. On post-mortem analysis no evidence of vasculitic organ damage was found. <strong>Conclusions:</strong> The patient showed rapid clinical response to imlifidase treatment. This effect was supported by rapid ANCA decrease and astic inhibition of neutrophil activation after ANCA cleavage in-vitro. Thus, imlifidase holds great potential of severe acute ANCA-associated vasculitis. We are currently designing an open label phase II study investigating the ug’s potential. <strong>Disclosures:</strong> JS, PE and AS are currently designing a phase II clinical study on imlifidase in ANCA associated vasculitis. All other authors disclose no conflicts of interests. Figure 1 (A) Imlifidase treatment resulted in rapid clearance of ANCA and total IgG. (B) In-vitro treatment with imlifidase significantly inhibited monoclonal ANCA-mediated activation of neutrophils and consequent release of reactive oxygen species. ANCA, anti-neutrophil cytoplasmic antibodies; IgG, immunoglobulin G; ctrl, control; MPO, myeloperoxidase; mAb, monoclonal antibody; PR3, proteinase 3