ANTI-CD25 MONOCLONAL ANTIBODY (MAB):AN IMMUNOMODULATING DRUG CANDIDATE FOR THE TREATMENT OF T-CELL MEDIATED DISEASES
Tesi di Dottorato
Data di Pubblicazione:
2014
Citazione:
ANTI-CD25 MONOCLONAL ANTIBODY (MAB):AN IMMUNOMODULATING DRUG CANDIDATE FOR THE TREATMENT OF T-CELL MEDIATED DISEASES / M. Montanini ; tutor: A. E. Panerai ; co-tutor: M. Onidi ; coordinator: A. E. Panerai. Università degli Studi di Milano, 2014 Dec 15. 27. ciclo, Anno Accademico 2014. [10.13130/montanini-melissa_phd2014-12-15].
Abstract:
INTRODUCTION AND BACKGROUND
Anti-CD25 is a fully human IgG1 kappa monoclonal antibody (mAb) against the alpha subunit of the interleukin 2 receptor (IL2Rα, also known as CD25 or TAC antigen) of potential clinical interest in autoimmune diseases, including multiple sclerosis, uveitis, type 1 diabetes and psoriasis.
Anti-CD25 acts mainly by inhibiting the proliferation of T cells and by consequence T cell clonal expansion and cytokine production. IL2 is a potent immunomodulator whose major function is the activation of various cells of the immune system, i.e. T cells (including CD4+ CD25+ regulatory T cells), B cells, NK cells and macrophages, which express CD25 upon antigen stimulation.
Anti-CD25 is presented with a potential therapeutic application in T cell mediated diseases, including organ transplant rejection and autoimmune disease, such as multiple sclerosis (MS).
The key to immunotherapeutic success with an anti-CD25 is to elicit the correct balance of effector and regulatory T cells. Nevertheless, the effects of an anti-CD25 antibody on the balance between pro-inflammatory T cells versus anti-inflammatory regulatory T cells are still unclear.
The potential advantages of Anti-CD25 are the high affinity for human CD25 and the fact that it is a fully humanized mAb, potentially less immunogenic, leading to longer duration of therapeutic effect.It is difficult to foresee which subpopulation of CD25 cells will be the most inhibited by blocking the IL-2Rα as a consequence of in vivo administration of Anti-CD25 mAb. Such aspects were investigated in non-human primates.
The ICH S6 guidance providing general principles for designing scientifically acceptable preclinical safety evaluation programs, to support clinical development and marketing authorization, was followed.
The purpose of the thesis was to assess the potential adverse effects resulting from the repeated
administration of Anti-CD25 mAb in Cynomolgus monkeys.
Selection of the relevant animal species for preclinical safety studies was based first on interspecies amino-acid sequence homology of CD25 extracellular domain. The capacity of Anti-CD25 to bind monkey (Rhesus, Cynomolgus and marmoset), minipig, mouse, rat and rabbit CD25 receptor expressed on CD3+ T cells was evaluated using resting or activated Peripheral Blood Mononuclear Cells (PBMCs).
The results obtained from Anti-CD25 cross-reactivity evaluation to PBMCs showed that Cynomolgus monkey was the only species where binding to CD25-bearing cells was shown at potentially relevant in vivo concentrations. Therefore the Cynomolgus monkey was considered the relevant species to be used in the preclinical development program of Anti-CD25.
EXPERIMENTAL DESIGN
The thesis will show data from a study where Anti-CD25 mAb was given by intravenous route (i.v.) at doses of 5, 25, and 125 mg/kg or subcutaneously (s.c.) at a dose of 75 mg/kg to 22 males and 22 females (4 animals/sex for groups 1, 2, and 3 and 5 animals/sex for groups 4 and 5) once a week for 4 consecutive weeks (total of 5 doses) as shown in the table below:
Group Doses Volume of administr. Concentr. In vehicle No. of males No. of females Group
(mg /kg/ week) (ml/Kg) (mg/ml) identification
[admin.Route]
---------------------------------------------------------------------------------------------------------------------------------------------------------------
1 0 (vehicle) [IV] 2 0 4 4 white
Tipologia IRIS:
Tesi di dottorato
Keywords:
Interleukin-2; Anti-CD25; Cynomolgus monkey
Elenco autori:
M. Montanini
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