The purpose of this study was to evaluate and compare the kinetics, biodistribution, and tumor-depicting properties of three intact indium-111-labeled murine monoclonal antibodies (MoAb) and to determine if use of In-111-labeled F(ab')2 fragments of one of them had advantages over its intact counterpart for immunoscintigraphy. Ten patients with prostate cancer were studied with an anti-prostatic acid phosphatase MoAb (PAY-276), with a resultant tumor detection rate of 15%. Twenty-eight patients with melanoma were studied with ZME-018, a MoAb that targets the KD-240 melanoma antigen. Forty-three percent of the known lesions were detected. Forty patients with carcinoembryonic antigen (CEA)-producing tumors were studied, 24 with intact ZCE-025, and anti-CEA MoAb, and 16 with its F(ab')2 fragment. With use of intact ZCE-025, 34% of known lesions were detected versus 83% with its F(ab')2 fragment. The distribution of each MoAb appears unique unto itself with regard to kinetics, normal tissue distribution, and response to MoAb mass.

We have infused 13 111In-labeled murine IgG monoclonal antibodies (MAb) into 73 patients who had been diagnosed as having 7 types of cancers, and 3 111In-labeled human MAb into 8 patients with breast cancer. To each patient, 1.5-5 mCi attached to a maximum of 1 mg MAb had been given in a total MAb dose of 0.5-500 mg. The most encouraging overall results have been obtained with anti-human T-cell MAb T101 (33 of 33 tumor sites imaged in 5 patients), antimelanoma MAb P96.5 (47 of 88 sites imaged in 21 patients), anti-prostate MAb PSA399 (14 of 21 sites imaged in 4 patients), and anti-colon MAb ZCE025 (16 of 26 sites imaged in 12 patients). Poor imaging results were related to lower doses, reactivity with circulating cells, and limited antigen expression in various tumor sites. The problems involved in radioimmunodetection included low extraction of MAb from the serum by the tumor that resulted in poor tumor uptake of the radiopharmaceutical, and high background activity in the liver, heart, spleen, and gastrointestinal tract that made imaging difficult in those areas. Heterogeneous antigen production leaves some tumor deposits without targets, and the immunogenicity of the MAb limits use of these agents repetitively in humans. Nevertheless, these early results are encouraging for their potential diagnostic and therapeutic applications.

We report results of 24-h continuous infusions of murine monoclonal antibody T101 in six patients with chronic lymphocytic leukemia (CLL), and 10 with cutaneous T-cell lymphoma (CTCL), at doses of 10, 50, 100, or 500 mg. Similar side-effects were seen in CLL and CTCL, including direct toxic effects of therapy, such as fever, sweats, and chilling, and a 30% frequency of allergic manifestations. In vivo binding of T101 to target cells in blood, skin, lymph nodes, tumor masses, and bone marrow was demonstrated. Antigenic modulation occurred rapidly in all cases, and persisted throughout the infusion period. Peak serum T101 levels for equivalent doses were somewhat higher, and persisted longer in CTCL, perhaps because of differences in the number of circulating target cells. Antimouse antibodies were demonstrated in 5 of 10 CTCL vs. 0 of 6 CLL patients. In all five cases, there was a substantial component of T101 specificity in the antimouse response. Brief objective clinical responses were observed in 4 of 10 CTCL and 2 of 6 CLL patients. Acute anti-tumor effects of T101 were substantially more dramatic in CTCL than CLL, but appeared limited by antigenic modulation and the emergence of antimouse antibodies. In view of the in vivo binding and modulation, more durable anti-tumor effects may be achievable with cytotoxic immunoconjugates of this monoclonal antibody.

Toxicity was assessed during and following 186 infusions of various murine monoclonal antibodies (MoAbs) in 82 patients afflicted with 10 different malignancies. Doses ranged from 0.5 to 500 mg per infusion and were administered over 0.25-24 h. Reactions of varying degrees were noted in 27 patients (33%) during or following 57 (31%) infusions. For antibodies that reacted with circulating cells, toxicity was seen in 20/82 of the first infusions compared with 0/55 for patients receiving antibodies that did not react with circulating cells. A 25% decrease in white blood cells (WBC) was associated with side effects in 40/66 courses whereas only 9/81 courses were associated with any sort of toxicity when the WBC decreased by less than 25%. Fevers, rigors, chills, and diaphoresis were observed in 21-23% of patients, but only in association with removal of circulating cells that bound the antibody. Presumed hypersensitivity reactions, including urticaria, pruritus, bronchospasm, and anaphylaxis occurred in 15 patients (18%). The two episodes of bronchospasm and single episode of anaphylaxis occurred in patients treated more than once, at least 2 weeks after a previous treatment. There was no clear relationship between dose or rate of infusion and toxicity for these antibodies. We conclude that murine MoAbs can be given with an acceptable frequency of serious allergic reactions and that the biologic effects of specific antibody-antigen reactions may be a more significant source of toxicity for such antibodies.

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

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.

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.