Objectives: Recombinant human erythropoietin (rHuEPO) is indicated to treat anemia in chronic kidney disease (CKD) [1]. Nevertheless, due to its short half-life requires frequent administration. Pegylation is an efficient method to improve therapeutic proteins' pharmacokinetics (PK). However, pegylation can also affect protein biologic properties, including potency [2]. A semi-mechanistic PK/PD model was previously developed to evaluate four rHuEPO (ior®EPOCIM, MIRCERA®, and PEG-EPO 32 and 40 kDa) in rabbits [3]. To select the best candidate and anticipate their human biological effect, the model was scaled by distinguishing drug and biological system parameters both in healthy subjects and patients with CKD. Methods: A semi-mechanistic PK/PD model describing the effect of the four formulations on the time course of hematopoiesis was used as a starting point for the extrapolation [3]. PK parameters were extrapolated by allometric scaling. Drug-specific parameters related to the pharmacological effect (slope of the linear model and amplification factor) were considered identical between species, considering the high degree of homology of receptors between species. System-specific parameters (hematopoiesis mean transit time; baseline reticulocytes, red blood cells, hemoglobin) were extrapolated using human physiological values. The ability of the model to predict human behavior was evaluated using published data from MIRCERA®. Simulations were then performed at the MIRCERA® efficacious doses to evaluate HGB concentrations 90 days after administration in patients with different degrees of CKD. Results: All the pegylated formulations showed similar exposures in humans and rabbits at the different evaluated doses. The half-life of PEG-EPO 32 increased in ~52 h and ~1.44 h with respect to ior®EPOCIM and MIRCERA®, respectively. The half-life of PEG-EPO 40 increased in ~94 h and ~3 h with respect to ior®EPOCIM and MIRCERA®, respectively. After 3 months of a single dose administration MIRCERA®, PEG-EPO 32 and PEG-EPO 40, there was a significant increase on the RBC count and HGB levels concerning ior®EPOCIM. However, no significant differences were found between these three formulations. Conclusions: The results suggest that PEG-EPO 32 and PEG-EPO 40 will present similar behaviors in humans to MIRCERA® and a significant prolongation of the pharmacological effect for ior®EPOCIM. These promising formulations would significantly decrease the frequency of administrations up to approximately one month, even in patients with severe CKD. The strict distinction between drug- and system-dependent parameters is a key feature of PK/PD models allowing a more realistic interspecies extrapolation than empirical approaches. Based on the simulations, PEG-EPO 32 would be a better candidate for FIH trials due to the lower content of PEG (and thus lower production cost) and similar duration of the effect with respect to PEG-EPO 40.Citations: [1] Label Mircera® (methoxy polyethylene glycol-epoetin beta) injection, for intravenous or subcutaneous use) revised 04/2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125164s089lbl.pdf[2] Páez R, Amaro D, Castro F, Hernández Y, Ruiz G. Conjugate comprising erythropoietin and a branched polymer structure. Google Patents; 2016.[3] Reynaldo-Fernández G, Solozábal J, Amaro D, Fernández-Sánchez EM, Rodríguez-Vera L, Bermejo M, Mangas-Sanjuan V, Troconiz IF. Semi-mechanistic Pharmacokinetic/Pharmacodynamic model of three pegylated rHuEPO and ior®EPOCIM in New Zealand rabbits. Eur J Pharmaceutical Sciences, 2018(120) 123–132. [4] Jiu-Hong Li, Jun-Feng Luo,Ying Jiang, Yong-Jian Ma, Yong-Qiang Ji, Guo-Liang Zhu, Cong Zhou, Hong-Wei Chu, Hou-De Zhang. Red Blood Cell Lifespan Shortening in Patients with Early-Stage Chronic Kidney Disease. Kidney Blood Press Res 2019;44: 1158–1165.
Targeted and broadly applicable molecular targets are important for image guided surgery. Xenoantigens represent a particularly interesting class of targets. This study evaluates the xenoantigen N-glycolyl-neuraminic acid GM3 ganglioside (Neu5Gc-GM3) as a potential fluorescence-guided surgical tool. The antibody 14F7hT is conjugated to the near-infrared dye (IRDye800CW) and characterized under GLP conditions. The quality and stability of the 14F7hT-IRDye800CW probe was assessed. In vivo imaging using 14F7hT-IRDye800CW in mice with Neu5Gc GM3 positive and negative xenografts were compared to a control IgG-IRDye800CW probe targeting an epitope not present on the xenografts. Biodistribution, pharmacokinetics, and toxicity were evaluated. The 14F7hT-IRDye800CW probe was 98 ± 2
Nimotuzumab, a humanized monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated clinical benefit in various epithelial tumors. However, selecting the right patient populations remains a challenge, particularly when considering real-world treatment scenarios and diverse tumor types. This study aimed to identify clinical and demographic subgroups of patients with the highest survival benefit from Nimotuzumab, using decision tree models applied to integrated clinical trial data. A total of 1,871 patients diagnosed with head and neck, brain, and esophageal cancers were included from 19 studies (phases I to IV and observational). Survival-related variables were analyzed using decision tree algorithms, a machine learning method suited for revealing complex, non-linear patterns among clinical features. The models stratified patients based on baseline characteristics and treatment outcomes. The results revealed distinct predictive profiles for each cancer type. In head and neck cancer, survival was best predicted by race, disease status, use of radiotherapy, performance status, and toxic habits. In brain tumors, the most influential variables were age, performance status, and histological subtype. In esophageal cancer, survival was mainly determined by sex, histological diagnosis, and race. These variables consistently emerged as key decision nodes in the trained models. The novelty of this study lies in its use of a machine learning approach across multiple tumor types treated with the same targeted therapy, Nimotuzumab. It is also among the first to apply such methodology to real-world data from low- and middle-income countries. By generating interpretable decision trees, the study offers a practical tool for identifying patient subgroups that are most likely to benefit from EGFR-targeted treatment, thereby supporting more efficient, personalized cancer care. These findings reinforce the value of integrating data mining and artificial intelligence techniques into oncology to enhance treatment selection and improve patient outcomes.
The main limitations of cancer treatment with high doses of recombinant interleukin 2 (IL-2) are high toxicity and the undesired expansion of regulatory T cells. The generation of IL-2 mutated variants (muteins) with changes in the affinity for different chains of the IL-2 receptor (IL-2R) allows selective stimulation of effector cells while overcoming its toxicity. As increasing the IL-2 affinity for the IL-2R beta chain leads to better antitumor effect, we generated a group of these muteins using phage display technology, in a previous work. Recombinant Fc-fusion proteins, including these variants, resulted in improved developability properties and better in vivo effect than variants containing the IL-2 (IL-2Fc). Here, we assessed one such improved mutein, named superbeta 834 (SB834Fc), and performed a comprehensive characterization of its properties. This mutein showed a stronger antitumor effect than IL-2Fc in 5 murine tumor models: 3LL-D122, B16F10, CT26, MC38, and 4T1 at very low doses. Different from other IL-2 variants, SB834Fc, as single therapy, shows antitumor effect in a therapeutic injection scheme. This antitumor effect was coincident with strong stimulation of effector T cells in the spleen and in the tumor microenvironment, far above that observed with IL-2Fc, despite maintaining the same level of Treg stimulation. Additionally, induction of proliferation was demonstrated in CD8+ T cells isolated from human healthy donors, highlighting its translational value. These results support the SB834Fc fusion protein as a suitable candidate to develop a new cancer immunotherapy based in IL-2.
