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

For high-risk patients, particularly young or elderly patients, with diseases of the hematopoietic cells, allogeneic hematopoietic cell transplantation (HCT) is often the only potentially curative treatment option. In preparation, high-dose chemotherapy and, in selected cases, external beam radiotherapy (EBRT) are often used. Especially in high-risk patients, the increased toxicity profile of these forms of treatment can mean treatment failure and even death. With high-dose radioimmunotherapy, the bone marrow can be treated with significantly less stress on the body. For a promising therapy targeting CD66, good results in previous treatments were demonstrated, but there has been increased non-specific accumulation in the liver and kidneys. The objective of this work was to use a recent chelator variant to improve radiolabeling and reduce non-specific accumulation with unaltered bone marrow uptake. In this article, we describe the production and demonstrate the improved distribution of the radiolabeled antibody based on early promising patient data. 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 Y-90-labeled anti-CD66 mAb. RIT followed by conditioning and HCT was well tolerated. Based on these promising initial data, further prospective studies of [Y-90]Y-DTPA-Bn-CHX-A00 -anti-CD66-mAb-assisted conditioning in HCT are warranted.

Automated summary

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for high-risk patients with diseases of the hematopoietic cells. High-dose chemotherapy and external beam radiotherapy (EBRT) are commonly used in preparation, but they can have toxic effects, leading to treatment failure or even death. High-dose radioimmunotherapy offers a less stressful treatment option for the bone marrow. This study aims to improve radiolabeling and reduce non-specific accumulation using a chelator variant.