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Abstract: PO2267

Using Skin Biopsies to Measure Target Occupancy of a Renal Antifibrotic Monoclonal Antibody (mAb) in a Phase 1 Clinical Study

Session Information

Category: Pathology and Lab Medicine

  • 1602 Pathology and Lab Medicine: Clinical


  • Bowcutt, Rowann, UCB Pharma, Slough, United Kingdom
  • Johnston, Geoffrey I., UCB Pharma, Slough, United Kingdom
  • Huang, Linghong, UCB Pharma, Slough, United Kingdom
  • Song, James Zhizhan, Prisys Biotechnology, Shanghai, China
  • Schmidt, Tim S., UCB Pharma, Slough, United Kingdom
  • Bigley, Alison L., OracleBio, Chapelhall, United Kingdom
  • Ogg, Graham, University of Oxford, Oxford, Oxfordshire, United Kingdom
  • Wong, Eric, UCB Pharma, Slough, United Kingdom
  • Thomson, Elizabeth S., UCB Pharma, Slough, United Kingdom
  • Chan, Jane Yuen, UCB Pharma, Slough, United Kingdom
  • Raievska, Anastasiia, Veramed, London, United Kingdom
  • Johnson, Timothy Scott, UCB Pharma, Slough, United Kingdom

Defining the optimal dose of drug required to bind to its mechanistic target (target occupancy, TO) and affect a measurable distal event (target engagement, TE) in damaged kidney is a challenge in the development of anti-fibrotic therapies for chronic kidney disease (CKD). We aimed to identify an accessible surrogate human tissue to predict TO in the kidney, prior to application in a Phase 1 study.


We developed a ‘biopsy-on-biopsy’ approach in skin: a 3mm biopsy initiated a wound healing response; a 6mm biopsy at the same site, up to 6 days later, provided tissue where active healing/fibrotic processes were ongoing. This method was used to measure the TO of zampilimab, a humanized mAb specific for human transglutaminase 2 (TG2), in development for fibrosis in CKD. Primate skin TO was correlated with kidney TO and TE in a unilateral ureteric obstruction (UUO) model, before application in a single dose Phase 1 study (NCT02879877).
Following dosing of zampilimab, TO in skin biopsies and kidney was measured using a competitive immunofluorescence assay on cryosections. A TRITC-labeled mouse parent of zampilimab (DC1) and a FITC-labeled anti-TG2 antibody binding a distant epitope (DH2) were used. TO was measured by comparing the relative binding of DC1 (competitively inhibited by zampilimab administered in vivo) to DH2. TE in kidney was measured using a TG2 in-situ activity assay.


In a primate UUO-CKD model treated prophylactically with zampilimab, the ‘biopsy-on-biopsy’ method showed excellent correlation between TO in the kidney and healing skin (3 days post first biopsy). Importantly, TO and TG2 inhibition (TE) in the kidney were also highly correlated. Subsequent use in the zampilimab Phase 1 study generated data directly comparable to the preclinical model.


Our ‘biopsy-on-biopsy’ approach allows early identification of a dose range in Phase 1 studies where the target organ is inaccessible, and is applicable to other therapeutic mAbs intended for treatment of fibrotic kidney disease. A Phase 1/2 study of zampilimab in patients with post-renal transplant fibrosis is ongoing (NCT04335578).


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