Abstract
The objective of this study was to translate reaction conditions and quality control methods used for production of an astatine-211(211At)-labeled anti-CD45 monoclonal antibody (MAb) conjugate, 211At-BC8-B10, from the laboratory setting to cGMP production. Five separate materials were produced in the preparation of 211At-BC8-B10: (1) p-isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS), (2) anti-CD45 MAb, BC8, (3) BC8-B10 MAb conjugate, (4) [211At]NaAt, and (5) 211At-BC8-B10. The 211At-labeling reagent, B10-NCS, was synthesized as previously reported. BC8 was produced, then conjugated with B10-NCS under cGMP conditions to form BC8-B10. [211At]NaAt was produced by α-irradiation of Bi targets, followed by isolation of the 211At using a “wet chemistry” method. The clinical product, 211At-BC8-B10, was prepared by reacting [211At]NaAt with BC8-B10 in NH4OAc buffer (pH 5.5) for 2 min at room temperature, followed by size-exclusion chromatography purification. Quality control tests conducted on the 211At-BC8-B10 included evaluations for purity and identity, as well as pyrogen and sterility tests. Stability of the 211At-BC8-B10 in 25 mg/mL sodium ascorbate solution was evaluated at 1, 2, 4, 6 and 21 h post isolation. For qualification, three consecutive 211At-BC8-B10 clinical preparations were successfully conducted in the cGMP suite, and an additional cGMP clinical preparation was carried out to validate each step required to deliver 211At-BC8-B10 to a patient. These cGMP preparations provided 0.80–1.28 Gbq (21.5–34.5 mCi) of 211At-BC8-B10 with radiochemical purity of >97%. The preparations were found to be sterile and have a pyrogen level <0.50 EU/mL. Cell binding was retained by the 211At-BC8-B10. 211At-BC8-B10 in ascorbic acid solution demonstrated a radiochemical stability of >95% for up to 21 h at room temperature. The experiments conducted have defined conditions for translation of 211At-BC8-B10 production from the laboratory to cGMP suite. This study has allowed the initiation of a phase I/II clinical trial using 211At-BC8-B10 (NCT03128034).
Highlights
Allogeneic hematopoietic cell transplantation (HCT) is a widely used form of therapy for patients with advanced hematological malignancies
One approach that we have investigated is the use of monoclonal antibodies (MAbs) labeled with beta-emitting radionuclides [i.e. iodine-131 (131I) or yttrium-90 (90Y)] employing radioimmunotherapy (RIT) to deliver high doses of radiation directly to bone marrow (BM), spleen and other affected disease sites, while sparing other organs [1,2,3,4,5,6]
HPLC chromatography was used to verify the identity of the B10: (1) p-isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS) and show that its purity was greater than 90%
Summary
Allogeneic hematopoietic cell transplantation (HCT) is a widely used form of therapy for patients with advanced hematological malignancies. One approach that we have investigated is the use of monoclonal antibodies (MAbs) labeled with beta-emitting radionuclides [i.e. iodine-131 (131I) or yttrium-90 (90Y)] employing radioimmunotherapy (RIT) to deliver high doses of radiation directly to bone marrow (BM), spleen and other affected disease sites, while sparing other organs [1,2,3,4,5,6]. This approach has had success, an attractive alternative is the use of MAbs labeled with alpha-emitting radionuclides for conditioning prior to HCT. Encouraging results from the preclinical studies prompted investigation of the anti-CD45 MAb, BC8, labeled with 211At as part of an HCT conditioning regimen for patients with relapsed or refractory leukemia or MDS who have failed conventional front-line therapy
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