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Title: Mechanistic and pharmacodynamic studies of ADCT-301, an Antibody Drug Conjugate targeting CD25-expressing haematological malignancies
Author: Flynn, M. J.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Interleukin-2 receptor-α (IL-2R-α, CD25), one of a heterotrimer that makes up the IL-2R, plays a key role in signal transduction pathways involved in the pathogenesis of autoimmunity and graft rejection. In addition, the preponderance of CD25-positive cells in haematological malignancies and the relationship between increased CD25 expression and poor prognosis raise the possibility of using an anti-CD25 antibody to deliver a cytotoxin to these cells in patients. Clinical proof of concept for treatment of CD25-positive malignancies has previously been established using radioimmunoconjugates and immunotoxins utilising antibodies basiliximab and daclizumab. ADCT-301 is an ADC composed of human IgG1 HuMax®-TAC against CD25,stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine dimer warhead with a drug-antibody ratio of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma and leukemia cell lines. Once internalised, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell cycle arrest in G2/M and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. This is important as many lymphomas show heterogeneous CD25 expression. In vivo, a single-dose of ADCT-301 results in dose dependent and targeted antitumour activity against both subcutaneous and disseminated CD25-positive tumour models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin(Adcetris®) is observed. Dose-dependent increases in DNA cross-linking, γ-H2AX and PBD payload staining were observed in tumours in vivo indicating a role as relevant pharmacodynamic assays. Together these data support the clinical testing of ADCT-301.
Supervisor: Hartley, J. A. ; Meyer, T. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available