Complexation of Cm(III) with blood serum proteins: recombinant human serum albumin (rHSA)

The complexation of Cm(III) with the recombinant human serum albumin (rHSA) (characterized by single deletion of residue Asp-1), is studied in dependence of pH and rHSA concentration using time-resolved laser fluorescence spectroscopy (TRLFS). A Cm(III) rHSA species is formed between pH 6.4 and 10.0 with the conditional stability constant being logK = 6.47 at pH = 7.4. Competition titration experiments with Cu(II) and Zn(II) confirm complexation at the N-terminal binding site (NTS) of rHSA and exclude the involvement of the Multi-Metal Binding Site (MBS). Comparison with a previous study on Cm(III) interaction with native albumin, HSA, points out, that residue Asp-1 is involved in Cm(III) binding to HSA but is not crucial for Cm(III) complexation at the NTS. The results are of major importance for a better understanding of fundamental actinide-protein interaction mechanisms which are highly required for the identification and characterization of relevant distribution pathways of incorporated radionuclides.

Randomized and dose-escalation trials of recombinant human serum albumin /granulocyte colony-stimulating factor in patients with breast cancer receiving anthracycline-containing chemotherapy

Background To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents. Methods The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 μg, 2100 μg, and 2400 μg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 μg and rhG-CSF 5 μg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 μg, 1500 μg, and continuous rhG-CSF 5 μg/kg. Results Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 μg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 μg to 2400 μg, while the double delivery of HSA/G-CSF 2400 μg failed to meet the noninferiority in comparison with rhG-CSF. Conclusion The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 μg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial. Trial registration ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).