Oxidatively modified low-density lipoprotein (LDL) is present in atherosclerotic but not normal arteries and plays a crucial role in the pathogenesis and adverse consequences of atherosclerotic lesions. We previously generated a series of monoclonal antibodies (MoAb) against oxidation-specific neo-epitopes formed during the oxidative modification of LDL. MDA2, a prototype MoAb, recognizes malondialdehyde-lysine epitopes (eg, in malondialdehyde-modified LDL) within atherosclerotic lesions. We describe the in vivo characteristics of MDA2 and initial noninvasive imaging studies of atherosclerosis in rabbits.

This study was directed toward determining the pharmacokinetic fate of an IgG2a monoclonal antibody (MoAb). The 96.5 anti-melanoma MoAb was labeled with indium-111 and indium-114m and administered to BALB/c mice. The mice receiving111In MoAb were sacrificed at 4 and 72 h, while those receiving114mIn 96.5 MoAb (50-day physical half-life) were sacrificed at 4 h and 3, 15, and 30 days. Multiple tissues were counted against a standard of the injectate and the data expressed as percent injected dose per organ and percent total dose excreted in the urine and feces. The 111 In- and114mIn-labeled MoAbs had nearly identical distribution through 72 h. Over the 30-day period 25% of the 114mIn label was excreted in the urine and 50% eliminated in the feces. All of the tissues studied showed a decrease in114mln in the 30-day period. We conclude that the metabolic products of indium-labeled MoAbs, the indium itself, or a combination of both are eliminated from the tissues over a period of several weeks and do not accumulate to a significant extent in any single site.

This study was conducted to investigate alterations that occur in an indium/111 Fab′ of a monoclonal antibody following its in vivo administration. Patients were infused with 111 In-Fab′ of the monoclonal antibody ZCE-025. Serum and urine specimens were collected from these patients. Starting materials, serum, urine and controls samples were studied by electrophoresis. Animal distribution studies were performed in normal Balb/c mice and, in some cases, nude mice bearing a carcinoembryonic antigen (CEA)/producing human colon tumour since the antibody targets CEA. The studies indicated that the molecule circulated almost totally intact for at least 4 h and to a considerable extent for 24 h, with some evidence for in vivo fragmentation by 24 h. Evidence was also obtained suggesting the formation of a high molecular weight species in some patients. Shortly after infusion, some of the 111In in the urine appeared as the intact Fab′, but within hours the majority migrated electro-phoretically as low molecular weight species. We conclude that while the majority of the 111In-Fab′ of this particular antibody remains intact and immunoreactive following its administration, the molecule is structurally changed to some degree shortly after its infusion into humans. Since each monoclonal antibody is unique, the degree and rapidity of degradation of its Fab′ in vivo could vary markedly from the above and possibly adversely effect its utility as a radiopharmaceutical.

It is customary to begin discussions of radioimmunodetection by giving proper credit to those who pioneered the field. That being the case, I too will mention the works of the great Paul Ehrlich (1) and David Pressman (2) who are our intellectual fathers. In doing so however, I must tell you that we would have done them greater honor had we carried the field further than we have to date. With the possible exception of the invention of monoclonal antibody technology (3) and a few new labeling methods, we remain far from making the “magic bullet” concept a reality. Yet we have not been without effort. Since the time of Pressman’s early communications (1953), many reports have indicated that iodine-labeled anti-tumor antibodies could be acquired by tumors in various animal species (4–15). This work has been meritorious and confusing. For example, nonspecific globulins as well as specific antibodies localize in tumors (16). Further, non-globulin proteins such as fibrin (17–19) and fibrinogen (20–22), similarly localize in tumors, and have been used for imaging. Thus, there is a portion of the radiopharmaceutical uptake by the tumor which has a basis other than antigen:antibody interaction.

Haindl, Walter; Halpern, Samuel E.; Dillman, Robert O.; Hagan, Phillip L.; Beauregard, Jacquelyn; Clutter, Maureen L.; Amox, Diane G.; Ryan, Kevin; Bartholomew, Richard M.; Frincke, James M.; Carlo, Dennis J. Author Information

Pressman and Keighley1 demonstrated in 1948 that anti-kidney antibodies could be radio-labeled with 131I without loss of immunoreactivity, and when administered to an animal, localize renal tissue. In 1953, the same investigators detected a mouse osteo-sarcoma using radio-labeled anti-tumor antibodies.2 Since then, many reports have been published on uptake of radio-labeled anti-tumor antibodies in animal models.3–5

The purpose of these studies was to determine if prostate carcinoma (PC) and cutaneous T-cell lymphoma (CTCL) could be detected using the In-lll- MoAbs described in this paper. Murine IgG MoAbs were developed against prostatic acid phosphatase (PAP) and to an antigen present on human T-cells. The MoAbs were labeled with In-lll by a bifunctional chelation technique and administered (ad) intravenously to patients (PT) with PC and CTCL respectively. One mg or less of each MoAb was labeled with 1.5-5.0 mCi of In-111. Normal prostate tissue was visualized in 3 of 5 PT and 5 of 12 bone metastases were detected in a PT with PC. Outstanding definitions of lymph nodes was achieved in CTCL. The sequence of administration markedly altered the invivo kinetics of the IN-111-MoAb. Some toxicity was observed in CTCL patients but not in PT with PC. The authors conclude that the above MoAbs will target tumor and that the sequence and to some extent quantities of MoAb has an affect on the pharmacokinetics and tumor uptake of these two MoAbs.

The purpose of this study was to evaluate In-111–96.5 MoAb as a radiopharmaçeuticl (R) for the detection of melanoma (mel). The 96.5 MoAb targets a 97 kilodalton surface antigen on the mel cells. Labeling was by a bifunctional chelation technique, and resulted in 3–5 mCi of In-111 chelated to 1 mg of antibody (A). The R was administered (Ad) intravenously through a 30–120 minute period. Twenty-two studies were performed in 21 patients (PT), with one PT studied twice. In four PT, unlabeled A was Ad prior to the R. Other PT received from 2–19 mg of unlabeled A mixed with the R. Blood (B) was drawn at multiple times following the infusion to observe R kinetics, and to determine if serum chemistries indicated toxicity (tox). There was no evidence of tox from the R or carrier A. Increasing protein mass slowed the loss of In-111 from B, and appeared to improve lesion detection. 66% of the 73 lesions 1.5 cm or larger were detected. Eight metastases were detected which were not clinically suspected. Five metastases imaged were in the 0.5–1.0 cm size range. Two were scalp metastases, and three were lymph nodes in the anterior cervical triangle of the neck. Liver uptake was a major cause of failure of the R as lesions could not be resolved if they occurred in the liver. We conclude that In-111–96.5 MoAb shows promise as a R for the detection of mel, and warrants further study.

Eleven patients with colorectal carcinoma were studied, 4 with primary, 7 with recurrent (1) or metastatic lesions. After injection of 1,5mg of F(ab')/sub 2/ of monoclonal anti-CEA antibodied No 35 (n=9) or 202 (n=2) labeled with I-123 (p,5n) (3-4mCi) whole body distribution was measured on anterior and posterior views at 1,6,24,48 h. SPECT was performed with a dual head device at 6,24,48 h. F(ab')/sub 2/ No 202 showed relatively high bone marrow uptake and high urinary activity (74% of injected activity in 3 days), but low liver activity (x-bar 14% of whole body activity at 24 h ). With F(ab')/sub 2/ No 35 bone marrow activity was lower, mean relative liver uptake 17% and mean urinary activity 24%. In 2 surgical specimens tumor to normal tissue ratios were measured at day 5 post injection and found to be 6,8,15,9 for one, 3,5,7,2 for the other in comparison with mucosa, serosa, fat and blood respectively. All 5 localized carcinoma were detected by ECT, the best images being obtained at 24 h. On the 6 h scans 4 patients with liver metastases showed cold lesions which became positive on the 24 h ECT in 2 of them whereas the 2 others remainedmore » doubtful. 2 patients with liver involvement showed no uptake. In 1 patient under therapy 2 small lung metastases were not detected. 2/2 bone metastases showed tracer uptake 1 of them was previously unknown. High quality images can be obtained with this method already at 24 h but the detection of metastases especially in the liver is sometimes difficult.« less

The purpose of these pilot studies was to determine if prostate carcinoma (PC), colon carcinoma (CC), and cutaneous T-Cell lymphoma (CTCL) could be detected using the In-111-MoAbs described below. Murine IgG MoAbs targeted against prostatic acid phosphatase (PAP), carcinoembryonic antigen (CEA), and an antibody that often recognizes CTCL (MAT-65) were labeled with In-111, and administered (Ad) intravenously to patients (PT) with PC, CC and CTCL respectively. One mg or less of MoAb was labeled with 1.5 – 5.0 mCI of In-111 in a total MoAb dose of 1–5 mg of anti-PAP, 0.5 mg of anti CEA, and 50 mg of MAT-65. All the MoAbs were infused over a two hour period. In one CTCL case, In-111-MoAb was Ad prior to, and a few weeks later, after a 50 mg dose of unlabeled MoAb. The infusion of In-111-MoAb followed a 50 mg infusion of unlabeled MoAb in the second CTCL case. Normal prostate tissue was visualized in 3 of 5 PT and 2 of the bone metastases imaged. Metastases from CC were visualized in 1 of 3 PTS. Outstanding definition of lymph nodes was achieved in CTCL, and the sequence of Ad markedly altered in the in-vivo kinetics of the In-111-MoAb. Some toxicity was observed in CTCL PTS, however, anti PAP and anti CEA were not toxic. We conclude that the above MoAbs will target tumor, and that further clinical trails with higher quantities of anti-PAP and CEA protein are warranted.