Optimization of Radiolabeling of a [90Y]Y-Anti-CD66-Antibody for Radioimmunotherapy before Allogeneic Hematopoietic Cell Transplantation

Abstract

For patients with acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia, allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. In addition to standard conditioning regimens for HCT, high-dose radioimmunotherapy (RIT) offers the unique opportunity to selectively deliver a high dose of radiation to the bone marrow while limiting side effects. Modification of a CD66b-specific monoclonal antibody (mAb) with a DTPA-based chelating agent should improve the absorbed dose distribution during therapy. The stability and radioimmunoreactive fraction of the radiolabeled mAbs were determined. Before RIT, all patients underwent dosimetry to determine absorbed doses to bone marrow, kidneys, liver, and spleen. Scans were performed twenty-four hours after therapy for quality control. A radiochemical purity of >95% and acceptable radioimmunoreactivity was achieved. Absorbed organ doses for the liver and kidney were consequently improved compared to reported historical data. All patients tolerated RIT well with no treatment-related acute adverse events. Complete remission could be observed in 4/5 of the patients 3 months after RIT. Two patients developed delayed liver failure unrelated to the radioimmunotherapy. The improved conjugation and radiolabeling procedure resulted in excellent stability, radiochemical purity, and CD66-specific radioimmunoreactivity of ⁹⁰Y-labeled anti-CD66 mAb. RIT followed by conditioning and HCT was well tolerated. Based on these promising initial data, further prospective studies of [⁹⁰Y]Y-DTPA-Bn-CHX-A″-anti-CD66-mAb-assisted conditioning in HCT are warranted.

Keywords: anti-CD66 antibody; hematopoietic cell transplantation (HCT); myeloablation; p-SCN-Bn-CHX-A″-DTPA; radioimmunotherapy; yttrium-90.

Figure 1

Graphical visualization of the conjugation-reaction process of the anti-CD66-mAb with the chelator p-SCN-CHX-A″-DTPA (A) and the subsequent radiolabeling procedure of the DTPA-anti-CD66-mAb with the radiometal (⁹⁰Y, ¹¹¹In, ^99mTc) (B).

Figure 2

Exemplary radiochromatograms of the ⁹⁰Y-labeled anti-CD66-mAb before and after SEC-purification. Radiolabeled DTPA-CHX-A″-anti-CD66-mAb (anti-CD66) was detected at a retention time of ~8.5 min. A small fraction of radiolabeled mAb-complexes was observed at 7.5 min, while unbound ⁹⁰Y was seen at a retention time of 12.3 min. The unbound ⁹⁰Y fraction was reduced by SEC purification (color highlighted areas).

Figure 3

Post-therapy anterior and posterior images after RIT are shown for each patient (P1–P5). Whole-body planar scintigraphies were obtained 1 d after RIT started on a Siemens Symbia T2 using the ME collimator. For each patient image the scale was normalized to the individual liver value (100%).

Figure 4

Organ-absorbed doses (mean and standard deviation) (A) and ratios of the organ-absorbed doses to bone marrow dose (B) of [⁹⁰Y]Y-anti-CD66-mAb for the current treatments compared to the data published by Ringhoffer et al. [12]. Absorbed doses were determined and compared for bone marrow, kidneys, liver, and remainder. While uptake in the bone marrow as a target region was quite similar to the previous ⁹⁰Y-labeled mAb, non-specific uptake in liver and kidney was favorably reduced. This was also reflected in the results for total body. The preferred distribution was also suggested when comparing the ratio of organs to bone marrow.