α-Imaging Confirmed Efficient Targeting of CD45-Positive Cells After ²¹¹At-Radioimmunotherapy for Hematopoietic Cell Transplantation

Abstract

Alpha-radioimmunotherapy targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-211 (211At)-radioimmunotherapy, extending the analysis to include intra-organ 211At activity distribution and α-imaging-based small-scale dosimetry, along with immunohistochemical staining. Methods Eight normal dogs were injected with either 0.75 (n=5) or 1.00 mg/kg (n=3) of 211At-B10-CA12.10C12 (11.5–27.6 MBq/kg). Two were euthanized and necropsied 19–22 hours post injection (p.i.), and six received autologous HCT three days after 211At-radioimmunotherapy, following lymph node and bone marrow biopsies at 2–4 and/or 19 hours p.i. Blood was sampled to study toxicity and clearance; CD45 targeting was evaluated by flow cytometry. 211At localization and small-scale dosimetry were assessed using two α-imaging systems: α-camera and iQID. Results Uptake of 211At was highest in spleen (0.31–0.61 %IA/g), lymph nodes (0.02–0.16 %IA/g), liver (0.11–0.12 %IA/g), and marrow (0.06–0.08 %IA/g). Lymphocytes in blood and marrow were efficiently targeted using either MAb dose. Lymph nodes remained unsaturated, but displayed targeted 211At localization in T lymphocyte-rich areas. Absorbed doses to blood, marrow, and lymph nodes were estimated at 3.1, 2.4, and 3.4 Gy/166 MBq, respectively. All transplanted dogs experienced transient hepatic toxicity. Liver enzyme levels were temporarily elevated in 5 of 6 dogs; 1 treated with 1.00 mg MAb/kg developed ascites and was euthanized 136 days after HCT. Conclusion 211At-anti-CD45 radioimmunotherapy with 0.75 mg MAb/kg efficiently targeted blood and marrow without severe toxicity. Dosimetry calculations and observed radiation-induced effects indicated that sufficient 211At-B10-CA12.10C12 localization was achieved for efficient conditioning for HCT.

Targeting Tyrosine Phosphatases: Time to End the Stigma

“…Studies are currently ongoing to employ anti-CD45 mAbs to improve outcome during hematopoietic cell transplantation (HCT). These include efforts to reduce the conditioning regimen for patients undergoing allogeneic transplantation[61], minimizing graft-versus-host disease without need of total-body irradiation[62], and delivering α-emitting radionuclides to hematopoietic tissues[63,64]. …”

Actinide bioimaging in tissues: Comparison of emulsion and solid track autoradiography techniques with the iQID camera

“…This unique feature is essential for radiation dosimetry at the sub-tissue scale. Three-dimensional radiation dose has been estimated from iQID images of tissue sections and simulation of localized irradiation for application in targeted radiation therapy [27]. This method could be applied to reconstruct the radiation dose to tissues contaminated with actinides.…”

“…These recent techniques enable quantification of the activity distribution in tissue sections. They have been increasingly applied for research in targeted alpha radiotherapy [25–28], with derivation of absorbed dose estimates [27]. In the frame of internal contamination with actinides, re-analysis of archival tissues is important to answer new questions that could not be addressed with techniques from the past [29, 30].…”

Development of a transmission alpha particle dosimetry technique using A549 cells and a Ra‐223 source for targeted alpha therapy

“…1,2,[12][13][14] For alpha particles to deliver dose to a tumor, an alpha emitting radionuclide is chelated to a specific carrier molecule (typically a protein or antibody) that specifically targets the tumor cells, resulting in the tumor being traversed by alpha particles and receiving a radiation dose. 13 Although the use of TAT is gradually advancing, to our knowledge there are currently only two methods to detect alpha emissions and to determine biodistribution: the α-camera (which is an autoradiography system using scintillating technique and optical registration by a charge-coupled device) [15][16][17] and iQID camera (which combines a scintillator and an image intensifier). 17,18 However, limited measurements, using these techniques for cellular uptake, have been applied to dosimetry to date.…”