The Production, Quality Control, and Characterization of ZED8, a CD8-Specific 89Zr-Labeled Immuno-PET Clinical Imaging Agent.

Immuno-PET is a molecular imaging technique utilizing positron emission tomography (PET) to measure the biodistribution of an antibody species labeled with a radioactive isotope. When applied as a clinical imaging technique, an immuno-PET imaging agent must be manufactured with quality standards appropriate for regulatory approval. This paper describes methods relevant to the chemistry, manufacturing, and controls component of an immuno-PET regulatory filing, such as an investigational new drug application. Namely, the production, quality control, and characterization of the immuno-PET clinical imaging agent, ZED8, an 89Zr-labeled CD8-specific monovalent antibody as well as its desferrioxamine-conjugated precursor, CED8, is described and evaluated. PET imaging data in a human CD8-expressing tumor murine model is presented as a proof of concept that the imaging agent exhibits target specificity and comparable biodistribution across a range of desferrioxamine conjugate loads.

Complete regression of massive cardiac involvement associated with acute T cell leukemia following chemotheraphy.

Adult T cell leukemia/lymphomas are aggressive disorders, which infiltrate not only the bone marrow but extensively the visceral organs as well. A case with left ventricular systolic dysfunction with myocardial infiltration and massive pericardial effusion which was demonstrated with echocardiography is discussed. The patient responded well to pericardial drainage and subsequent chemotherapy. The dramatic improvement in echocardiographic findings after chemotherapy gave a clue to investigate suspected patients with aggressive leukemia and lymphomas for exclusion of leukemic infiltration of myocardium.

Primary adult T-cell leukemia/lymphoma of bone.

A 77-year-old man developed primary adult T-cell leukemia/lymphoma (ATL) of the bone with osteolytic lesions. A biopsy of the lesion revealed proliferation of atypical, large lymphoid cells with a local increase of osteoclasts. The clonal integration of human T-lymphotropic virus type I proviral DNA revealed the tumor cells to be ATL. They produced macrophage inflammatory protein 1alpha (MIP-1alpha) but not parathyroid hormone-related protein or other osteoclast-activating factors. Because MIP-1 produced by tumor cells enhances the expression of receptor activator of nuclear factor kappaB ligand (RANKL) of local osteoblasts and stromal cells, even of tumor cells, the increase of osteoclasts in the close vicinity of ATL cells was considered to result in local bone destruction.

Numerous sites of increased uptake shown on bone scintigraphy in a case of adult T-cell leukemia.

Bone scintigraphy was performed in a 69-year-old male patient with adult T-cell leukemia suffering from right lower limb pain. Numerous sites of increased uptake were seen in the skull, left clavicle, bilateral humeri, bilateral radii and right femur and tibia. Bone radiographs showed multiple osteolytic lesions, most of which corresponded to the abnormal deposits on the bone scans with 740 MBq of 99mTc-hydroxymethylene diphosphonate. This pattern is rarely reported, but bone involvement of adult T-cell leukemia is not uncommon. Bone involvement was remarkable on the appendicular skeleton when compared with common metastatic bone tumors. Bone scintigraphy may be useful in detecting bone involvement in adult T-cell leukemia.

Primary adult T cell leukemia of bone: two patients with primary bone lesion showing monoclonal integration of HTLV-I proviral DNA.

Adult T cell leukemia (ATL), a neoplasm of mature helper T lymphocytes is etiologically associated with human T lymphotropic virus type-I (HTLV-I). ATL cells infiltrate various organs, the lung, skin, central nervous system, gastrointestinal tract, and bone, causing various clinical manifestations. Two unusual cases of ATL, in which lytic bone lesion was the primary site of ATL, are described. One patient had multiple lytic lesions in bones without any involvement of other organs, and the other patient had a bone lesion in the right radius, which disappeared after chemotherapy. In both cases, monoclonal integration of HTLV-I provirus was demonstrated in the genomic DNA from each bone lesion. Although their clinical courses and pathological findings were different, ATL in both patients began as a bone lesion, showing that primary lymphoma of bone can be manifested in ATL cases.

Radioimmunodetection of human leukemia with anti-interleukin-2 receptor antibody in severe combined immunodeficiency mice.

Anti-Tac monoclonal antibody recognizes human interleukin-2 receptor, which is overexpressed in leukemic cells of most adult T-cell leukemia (ATL) patients. To examine the potency of anti-Tac for targeting of ATL, biodistributions of intravenously administered 125I- and 111In-labeled anti-Tac were examined in severe combined immunodeficiency (SCID) mice inoculated with ATL cells. Significant amounts of radiolabeled anti-Tac were found in the spleen and thymus. The trafficking of ATL cells in SCID mice was detected using 111In-oxine-labeled ATL cells. These results were coincident with the histologically confirmed infiltration of ATL cells. The radiolabeled anti-Tac seemed potent for targeting of ATL.

Localization and biodistribution of conjugate ATG-Dex-DNR in nude mice as models for human leukemia.

131I-labelled anti-thymoglobuline (ATG), 131I-labelled immunoconjugate ATG-Dex-DNR and 131I-labelled Ts-MoAb as control antibody, respectively, were injected by intraperitoneal (i.p.) administration into nude mice used as models for human T-cell leukemia. SPECT imaging was performed from day 1 to day 8 following i.p. injection. The results showed that radioimmunoimaging of human tumor xenografts was clearest day 3 after injection in both of ATG and ATG-Dex-DNR groups, whereas it's not the case in Ts-MoAb group. Nude mice were killed 8th day after injection with antibody or conjugate. The tumor, as well as different dissected normal organs including heart, liver, lungs, kidney, femur and intestine, were harvested, weighed precisely, and radioiodine-counted. T/NT ratios in experimental group was greater than 1.0 (ranged from 1.246-7.865), and in control group they were less than 1.0 (ranged from 0.263-0.757, except for tumor/femur ratio). Our results indicated that ATG and ATG-Dex-DNR had specific affinity to cell line of T-cell leukemia CEM.

Adult T-cell leukemia with a solitary lung mass.

A 49-year-old woman was admitted to the hospital with supraclavicular lymph node swelling. On a chest x-ray film, a 4 x 4-cm nodular shadow was observed in the right middle lung field. The white blood cell count was 10,100/cu mm, showing 44 percent abnormal lymphocytes with lobulated nuclei. Since HTLV-I antibodies were markedly positive, she was diagnosed as having ATL. Transbronchial tumor biopsy revealed accumulation of ATL cells. Our patient is the first case with only a large nodular accumulation of ATL cells without diffuse infiltration of the cells in the lung.

Hepatic photopenia in gallium imaging.

Although Ga-67 has been used extensively in imaging many different conditions, much is yet unknown about the mechanisms by which gallium concentrates preferentially in tissues such as the liver. This paper reports three patients with markedly diminished hepatic uptake of gallium. The cases are examined in light of published data demonstrating such factors as transferrin levels, radiation, and chemotherapeutic agents as altering the hepatic uptake of gallium. Of the many factors believed to influence the biodistribution of gallium, none can definitively account for the lack of hepatic uptake in these patients.