Wanjeh, David (2018) Optimization of freeze-drying method for therapeutic Rituximab-1B4M kit, radiopharmaceutical for targeted radioimmunotherapy of CD20+ lymphomas. Masters thesis, Goce Delcev University Stip.
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Lektorirano_MASTER THESIS RADIOPHARMACY David Mwanza Wanjeh.pdf Download (1MB) | Preview |
Abstract
Therapeutic monoclonal antibodies (TMAs) continue to grow tremendously in their clinical importance since their first application more than thirty years ago (Ecker et al., 2015). The oncological application of monoclonal antibodies has taken the same trend since the approval of the rituximab, the first approved TMA for cancer therapy (Reichert and Valge-Archer, 2007). Anti-tumor TMAs are particularly attractive for their high specificity in antigen binding. Therefore, they offer themselves as a clinically effective tool for targeting therapy to particular tumor cell types with minimal inhibition of non-target cells. Compared to the conventional small molecule anti-tumor agents, TMAs mechanism of tumor cytotoxicity is achieved through the activation of the immune system in addition to the direct tumor cell inhibition. Indeed, the in vivo efficacy of the anti-tumor TMAs has been shown to be higher than for conventional small molecule therapeutic agents for some lymphoma types (Else et al., 2012).
However, antibody therapy is not always effective. In some patient types, tumors may be refractory or resistant to TMAs or they may relapse. A number of strategies have been devised for the improvement of TMAs for such patient types. The approaches include, among others, the synthesis of antibody-drug conjugates and therapeutic radio-antibodies; some of these have already obtained regulatory approval for clinical application (Ujjani and Cheson, 2013).
Thus, two radiolabeled TMAs have so far found approval for clinical application, ibritumomab/90Y-ibritumomab tiuxetan and tositumomab/131I-tositumomab for the treatment of refractory or relapsed low grade CD20+ Non-Hodgkin’s Lymphomas (NHLs). The benefit of using TMAs radiolabeled with energetic particle emitting radioisotopes for the targeted tumor treatment is the additional opportunity to kill other tumors cells in the vicinity of the CD20+ tumor cells through crossfire and bystander effects. The ability to kill non-CD20+ tumor cells is highly beneficial, especially where the tumor exhibits heterogeneity in antigen expression. The tissue range of the emitted particles, their therapeutic efficacy and also normal tissue toxicity depend on the energy of the particles, which in turn is dictated by the particular radioisotope used.
A variety of suitable particle emitting radioisotopes is available for radiolabeling TMAs for the radioimmunotherapy (RIT) of tumors. These radioisotopes differ in terms of
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their decay modes, half-lives, particle energies and chemistry. In the RIT of CD20+ NHL, products that have seen approval for clinical application have been radiolabeled with the beta-emitters; Yttrium-90 (ibritumomab/90Y-ibritumomab tiuxetan) (“Approval Letter - Ibritumomab Tiuxetan, (Zevalin), IDEC Pharmaceuticals Corp - ucm113489.pdf,” n.d.) and Iodine-131 (tositumomab/131I-tositumomab) (“Therapeutic Biologic Applications (BLA) > Bexxar Approval Letter 6/27/03,” n.d.). Other clinically useful radioisotopes include Lutetium-177, Re-188, Samarium-153, etc. Generally, radioisotopes emitting long tissue range beta particles may be more useful for large tumor masses, while low tissue range beta particle emitters may be more useful for small tumor masses, including small metastatic lesions.
Radiolabeling of the TMAs can be achieved either directly or indirectly (Sugar et al., 2014). The direct approach is feasible for radioiodination but it is unsuitable for most radiometal labeling work because TMAs lack strong chelating groups to strongly bind the radiometal cations. For clinical usefulness of a TMA based radiopharmaceutical, the in vivo thermodynamic and kinetic stability of the metal complex is vital. Hence, derivatization of the TMAs to introduce strong chelator groups is necessary. Chelator groups that are potentially useful for a variety of radiometals have already been synthesized and widely studied (Brechbiel, 2008). For trivalent radiometal cations such as lutetium or yttrium, the commonest are DOTA derivatives and DTPA derivatives. As an already available clinical example, derivatization of ibritumomab was done with tiuxetan for radiolabeling with yttrium-90 (Jacobs, 2007).
All the currently approved RIT radiopharmaceuticals are formulated as liquid preparations. The challenges associated with such formulations are stability of the antibody in storage and a cumbersome radiolabeling process. The stability of antibodies in their low concentration solutions is low, hence their short shelf life and strict cold-chain transportation and storage. The cumbersome radiolabeling procedure increases the risk of mix-ups and poor quality of the injected preparation. For that reason, it is necessary to produce a more stable preparation that is easier to radiolabel, preferably in a one-step process; it has a long shelf life in storage and does not require strict coldchain conditions during distribution. One strategy is to use the freeze drying technology.
Freeze drying is a widely applied, widely studied technology. It helps to produce dry
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preparations of thermolabile drug substances with high porosity and fast dissolution during reconstitution. Its application in the production of biotechnological pharmaceutical products is already well established (Ekenlebie et al., 2016). The freeze drying process removes almost all the water from the solution, thereby yielding a more stable product that weighs less, and is easy and fast to reconstitute.
In our work, we intended to investigate the suitability of our freeze drying protocol for the preparation of a ready-to-use radiolabel freeze dried rituximab-1b4mDTPA kit radiopharmaceutical radiolabeling with yttrium-90 or lutetium-177
| Item Type: | Thesis (Masters) |
|---|---|
| Subjects: | Medical and Health Sciences > Other medical sciences |
| Divisions: | Faculty of Medical Science |
| Depositing User: | Katerina Hadzi-Vasileva |
| Date Deposited: | 05 Feb 2019 08:59 |
| Last Modified: | 20 Aug 2019 12:55 |
| URI: | https://eprints.ugd.edu.mk/id/eprint/21402 |
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