Biomedical subjects

R M Sharkey

Publications and source records attributed to R M Sharkey.

At least 37 records · Page 2Linked to original sources

PubMed1997

Defining the optimal spacing between repeat radioantibody doses in experimental models: is there an accurate measurement for hematopoietic recovery?

BACKGROUND: Single doses of radioantibody are effective at treating single cells or small clusters of cancer cells. However, large tumor masses require either multiple doses of radioantibody or a multimodal approach to therapy using two or more therapeutic agents. Timing of the second dose in a multiple cycle scheme or the second treatment in a multimodal protocol will depend on recovery from toxicity associated with the first treatment. METHODS: BALB/c mice were dosed with a maximal tolerated dose (MTD) of I-131-MN-14 anti-carcinoembryonic antigen immunoglobulin G (IgG) (250 microCi) or F(ab')2 (1.2 mCi). Mice were redosed with the MTD at one of four time points, either Day 28, 35, 42, or 49 after IgG or Day 14, 21, 28, or 35 after F(ab')2. Survival was monitored to determine the earliest time to redose without lethality. Several studies were then performed to identify an accurate measure of true myelorecovery. Mice were bled retroorbitally on the day of the first dose and at weekly intervals thereafter. Total peripheral white blood cell counts, granulocyte counts, and lymphocyte counts were determined for each animal. GR-1hi expression (percentage of positive cells) and mean channel florescence were determined by FACScan analysis of a blood sample incubated with fluorescein isothiocyanate-anti-mouse Ly-6G (GR-1). In other studies, two mice were killed weekly from a group treated with a single MTD of radioantibody. The weights of their spleens and thymus glands were determined. At that time, femoral marrow was collected from these animals and plated in Methocult M3430 methylcellulose medium (Stemcell Technologies, Vancouver, Canada), and total colony-forming cells in culture were determined. Another population of mice was used to assess normal tissue metabolic activity following radioantibody therapy by quantitating the 4-hour utilization of I-125-dUrd. RESULTS: The ability to redose mice with a second MTD of 1-131-IgG or F(ab')2 required 49 days and 35 days, respectively. Granulocyte and lymphocyte counts did not accurately predict myelorecovery from the first dose. Hematopoietic tissue weight, tissue metabolic activity, and marrow colony forming cells all suggested that redosing was possible 1-2 weeks before it could actually be done without lethality. Percent of cells expressing GR-1hi (>60%) and absolute numbers of GR-1hi cells (>1400 cells/mm3) suggested myelorecovery in most animals. A greater degree of accuracy was achieved when trends in GR-1hi expression were noted over 2 or more weeks (i.e., the absolute amount of GR-1hi had to exceed levels in untreated mice, as evidence that the hyperproliferative phase of recovery was complete). CONCLUSIONS: The only approach that accurately predicted the ability to retreat with myelosuppressive therapy without risk of lethality was an increase in GR-1hi-positive cells above untreated levels. Other approaches are currently being investigated, including the expression of proliferation antigens (e.g., proliferating cell nuclear antigen and Ki-67) in both murine and human samples and differentiation antigens (CD33 and CD34) in humans.

Animals↗

PubMed1997

Can occult metastases be treated by radioimmunotherapy?

BACKGROUND: Tumor lesions in the millimeter (mm) range may escape detection with nuclear medicine imaging methods (including single photon emission computed tomography [SPECT]) using radiolabeled monoclonal antibodies (MoAbs). We hypothesized that these lesions still could receive a potentially therapeutic radiation absorbed dose, and therefore should be treated, despite the lack of detection. METHODS: To simulate this situation, 2-mm beads (0.004 mL) containing approximately 1.15 microCi of iodine-131 (131I) were used. The beads were placed centrally in a 1200-mL liver phantom containing approximately 3 mCi of 131I. The resultant activity concentration on the beads was approximately 288 microCi/mL compared with approximately 2.5 microCi/mL in the phantom, corresponding to a maximum tumor uptake of approximately 0.3% injected dose per gram (%ID/g) if 100 mCi of 131I-labeled immunoglobulin G were administered. The phantom, containing the beads, was imaged by both planar and SPECT techniques at hypothetical Day 1 (time of maximum tumor uptake) and at hypothetical Day 7 to examine the improved target-to-nontarget ratio over time. In addition to imaging the beads, the radiation absorbed dose to the simulated lesions from the beta component emissions of 131I was calculated using absorbed fractions based on Berger's point kernels. RESULTS: Regardless of the conditions used, the beads could not be observed by either planar or SPECT imaging. However, the radiation-absorbed dose to the simulated lesion was calculated to be as high as approximately 6200 centigray (cGy), with an average dose rate of approximately 89.5 cGy/hour. CONCLUSIONS: This simulation demonstrates that a relatively high absorbed dose and dose rate can be delivered to mm-sized lesions not observed by conventional nuclear imaging methods, and that these lesions should be considered for radioimmunotherapy with 1311 MoAbs. However, for micrometastases of <1 mm, other radionuclides with shorter path length beta particles than 131I, Auger electrons, or alpha particles should be considered.

Humans↗

PubMed1997

Factors influencing hematologic toxicity of radioimmunotherapy with 131I-labeled anti-carcinoembryonic antigen antibodies.

BACKGROUND: Several investigators have reported a considerable variability in the observed hematologic toxicity after radioimmunotherapy (RAIT) with monoclonal antibodies (MoAb) given at similar amounts of radioactivity based on body surface area and/or similar radiation absorbed doses given to the red marrow. The authors investigated various factors potentially affecting hematologic toxicity after RAIT with 131I-labeled anti-carcinoembryonic antigen (CEA) MoAb to identify the statistically significant factors from those commonly perceived clinically to substantially contribute to this toxicity. METHODS: Ninety-nine patients who received 131I-labeled anti-CEA MoAb for the treatment of CEA-producing cancers were assessed for platelet and white blood cell toxicity based on the common Radiation Therapy Oncology Group criteria. Multivariate regression analysis was used to identify the statistically significant factors affecting toxicity among the following variables: red marrow dose, baseline platelet and white blood cell counts, bone and/or marrow metastases, prior chemotherapy or radiotherapy, timing of prior chemotherapy or radiotherapy in relationship to RAIT, type and number of prior chemotherapeutic regimens, age, sex, antibody form, and cancer type. RESULTS AND CONCLUSIONS: Red marrow dose, baseline platelet or white blood cell counts, multiple bone and/or marrow metastases, and chemotherapy 3-6 months before RAIT were the only four significant factors affecting hematologic toxicity according to multivariate analysis. The identification of bone and/or marrow metastases and recent chemotherapy as significant factors for hematologic toxicity could be important in the design of future clinical trials.

Adolescent↗

PubMed1997

Selection of radioimmunoconjugates for the therapy of well-established or micrometastatic colon carcinoma.

In order to optimize radioimmunotherapy (RAIT) as a cancer-treatment modality, it is necessary to select the appropriate radionuclide and antibody carrier. We evaluated the therapeutic potential of a single cycle of Mu-9 anti-CSAp monoclonal antibody (MAb) labeled with 3 different radionuclides, 131I, 90Y and 188Re. Intact antibodies and bivalent fragments with different blood clearance kinetics, normal organ distribution and varying tumor accretion and retention are also evaluated. Efficacy of treatment for large and small tumor burden was assessed in nude mice bearing s.c. GW-39 human colonic-carcinoma xenografts or intrapulmonary micrometastatic GW-39 colonies at the maximal tolerated dose of each agent. The magnitude and duration of myelosuppression associated with each radioantibody was considered by monitoring peripheral blood counts, marrow colony-forming unit activity and hematopoietic tissue weight. Radiation-dose estimates were calculated based on the kinetics of antibody accretion and elimination from tumor and normal tissues, and the results were correlated with tumoricidal activity and dose-limiting toxicity results. These studies, therefore, represent a detailed analysis, in a well-defined experimental tumor system, of several parameters (antibody form, radioisotope, tumor size) influencing the overall outcome of RAIT using equitoxic doses. It was found that myelosuppression is the primary dose-limiting toxicity for all radioantibodies except 90Y-F(ab')2, even though the different agents showed varied organ distribution. In a single-cycle treatment schedule of Mu-9 MAb, the 131I-labeled IgG is the radioimmunoconjugate of choice for the treatment of s.c. and intrapulmonary growth of the GW-39 human colonic-carcinoma xenograft in nude mice.

Animals↗

PubMed1997

Application of cytokine intervention for improved radio-antibody dose delivery.

The goal of our studies was to determine whether administration of IL-1/GM-CSF to mice could reduce radio-antibody-induced myelosuppression and allow either dose escalation of radio-antibody using 131I, 90Y or 188Re conjugated to either intact antibody or bivalent fragments or more frequent dosing with 131I-IgG. Survival, peripheral blood counts, hematopoietic tissue weight and number of marrow CFCs were used to determine the ability to dose-intensify with a single dose or to reduce the spacing between doses. In this report, we show that in the absence of cytokines, 2 cycles of 131I-IgG spaced at 28, 35, 42 and 49 days resulted in 100%, 100%, 40% and 0% lethality, respectively. In contrast, cytokine intervention reduced lethality to 45%, 20%, 0% and 0% at the same time intervals between doses. Thus, the use of cytokines permits at least a 1 week earlier redosing of 131I-IgG. Cytokine intervention also has reduced the magnitude of myelosuppression, as measured by neutropenia and thrombocytopenia, thus permitting intensification of single doses of radio-iodinated intact antibodies, bivalent fragments and 90Y-IgG by at least 30%, 50% and 25%, respectively. However, cytokines were not effective at permitting dose escalation of either 90Y-F(ab')2 or 188Re-IgG. Further optimization of the dose schedule of cytokine administration needs to be explored for these 2 nuclide-antibody forms.

Animals↗

PubMed1997

The advantage of residualizing radiolabels for targeting B-cell lymphomas with a radiolabeled anti-CD22 monoclonal antibody.

CD22 antibodies (Abs) bound to B-cell lymphomas are known to be internalized and catabolized rapidly. Therefore, it would be expected that use of CD22 as a target for radioimmunotherapy should be enhanced by the use of "residualizing" radiolabels, which are trapped within the cell after catabolism of the Ab to which they had been conjugated. Our study was intended to evaluate this hypothesis using Ab LL2. In initial experiments, we found that LL2 binding was strongly temperature dependent, with approximately 15-fold greater binding at 37 degrees C than at 0 degrees C. A series of experiments suggested that this difference is due to a conformational change in the antigen at low temperature, so that the LL2 epitope is partially blocked. In vitro, residualizing labels-including 125I-dilactitol tyramine and 111In-DTPA-were retained by cells much longer than a conventional iodine label. In vivo, residualizing labels also showed a marked advantage in terms of uptake by Ramos B-cell lymphoma xenografts in nude mice. However, the absolute Ab uptake by xenografts was quite low, in comparison with results obtained with many carcinoma xenografts, which appears to be due in part to vascular properties of the B-cell lymphoma xenografts.

Animals↗

PubMed1997

Reduction in the duration of myelotoxicity associated with radioimmunotherapy with infusions of the hemoregulatory peptide, HP5b in mice.

The hemoregulatory peptide, pGlu-Glu-Asp-Cys-Lys (pEEDCK or HP5b), has been shown to reversibly inhibit the proliferation of bone-marrow progenitor cells, and has been reported to protect mice from the myelotoxicity associated with ara-C, a chemotherapeutic agent. We undertook to use this reagent to reduce radioimmunotherapy(RAIT)-associated bone-marrow toxicity by suppressing hematopoiesis during the critical period when bone marrow is exposed to radiation. The reported studies optimize the use of HP5b to reduce the duration of neutropenia and thrombocytopenia. We found that 3.6 micrograms/day of HP5b administered through a continuous 7d mini-osmotic pump, together with a bolus dose of 3.6 micrograms 3 hours before the radioantibody dose, gave the best effect, as measured by neutrophil counts on day 28 post RAIT. With sub-lethal doses of RAIT, the period of neutropenia was reduced by 2 weeks, and there appeared to be more rapid recovery of morphologically mature myeloid cells. The peptide, however, does not appear to alleviate the lymphotoxicity associated with RAIT. No adverse effects have been noted from continuous infusions of the peptide. In the past, we reported that cytokines (IL-I/GM-CSF) are not marrow-restorative when given after RAIT. However, an additive effect is observed when HP5b infusions are combined with post-RAIT cytokine administration, suggesting that a significant pool of bone-marrow progenitor cells remains when HP5b is co-administered with RAIT. Thus, HP5b is an alternate approach to reducing myelotoxicity, and may be used in combination with cytokines to further reduce the duration of myelosuppression.

Animals↗

PubMed1997

Prospects of radioimmunotherapy in epithelial ovarian cancer: results with iodine-131-labeled murine and humanized MN-14 anti-carcinoembryonic antigen monoclonal antibodies.

OBJECTIVES: Epithelial ovarian cancer (EOC) is known to produce carcinoembryonic antigen (CEA), and the plasma CEA level is frequently elevated in patients with advanced stage and bulk of tumor. This study reports the results of a phase I therapy trial with intravenously administered 131I-MN-14 anti-CEA monoclonal antibody (MAb) in patients with EOC. METHODS: Fourteen patients with advanced refractory EOC were given escalating intravenous doses (two received 30 mCi/m2, six 40 mCi/m2, and six 50 mCi/m2) of 131I-MN-14 IgG. All patients received a diagnostic study with 8 mCi (0.6 mg) of 131I-MN-14 IgG 1 week prior to their therapy infusion. Tumor targeting was assessed by external scintigraphy, toxicity according to the Radiation Therapy Oncology Group criteria, and therapy responses by CT and serum CA-125. RESULTS: The MAb scan was positive in all 14 treated patients. Myelosuppression was the only observed treatment-related toxicity. Dose-limiting toxicity, defined as grade 4 leukopenia or thrombocytopenia of any duration, or grade 3 leukopenia or thrombocytopenia of > 2 weeks, was not seen at the 30 or 40 mCi/m2 dose levels. However, 2 of 6 patients treated at 50 mCi/m2 had a grade 4 thrombocytopenia or a grade 3 thrombocytopenia lasting 18 days. Of the 14 patients, 1 with diffuse peritoneal implants of < or = 2 cm had a complete clinical remission by CT and CA-125 for 8 months, following an initial partial remission for 10 months, both at the 40 mCi/m2 dose level. Another patient had a mixed response for 1 month. CONCLUSION: MN-14 anti-CEA MAb is a suitable agent for tumor targeting and may have a therapeutic potential in patients with chemotherapy-refractive EOC, especially those with minimal disease.

Adult↗

PubMed1997

Advantage of residualizing radiolabels for an internalizing antibody against the B-cell lymphoma antigen, CD22.

LL2 is an anti-CD22 pan-B-cell monoclonal antibody which, when radiolabeled, has a high sensitivity for detecting B-cell, non-Hodgkin's lymphoma (NHL), as well as an antitumor efficacy in therapeutic applications. The aim of this study was to determine whether intracellularly retained radiolabels have an advantage in the diagnosis and therapy of lymphoma with LL2. In vitro studies showed that iodinated LL2 is intracellularly catabolized, with a rapid release of the radioiodine from the cell. In contrast, residualizing radiolabels, such as radioactive metals, are retained intracellularly for substantially longer. In vivo studies were performed using LL2-labeled with radioiodine by a non-residualizing (chloramine-T) or a residualizing method (dilactitol-tyramine, DLT), or with a radioactive metal (111In). The biodistribution of a mixture of 125I (non-residualizing chloramine-T compared to residualizing DLT), 111In-labeled LL2 murine IgG2a or its fragments [F(ab')2, Fab'], as well as its humanized, CDR-grafted form, was studied in nude mice bearing the RL human B-cell NHL cell line. Radiation doses were calculated from the biodistribution data according to the Medical International Radiation Dose scheme to assess the potential advantage for therapeutic applications. At all assay times, tumor uptake was higher with the residualizing labels (i.e., 111In and DLT-125I) than with the non-residualizing iodine label. For example, tumor/blood ratios of 111In-labeled IgG were 3.2-, 3.5- and 2.8-fold higher than for non-residualizing iodinated IgG on days 3, 7 and 14, respectively. Similar results were obtained for DLT-labeled IgG and fragments with residualized radiolabels. Tumor/organ ratios also were higher with residualizing labels. No significant differences in tumor, blood and organ uptake were observed between murine and humanized LL2. The conventionally iodinated anti-CD20 antibody, 1F5, had tumor uptake values comparable to those of iodinated LL2, the uptake of both antibodies being strongly dependent on tumor size. These data suggest that, with internalizing antibodies such as LL2, labeling with intracellularly retained isotopes has an advantage over released ones, which justifies further clinical trials with residualizing 111In-labeled LL2 for diagnosis, and residualizing 131I and 90Y labels for therapy.

Animals↗

PubMed1997

Improved selection of patients for reoperation for medullary thyroid cancer by imaging with radiolabeled anticarcinoembryonic antigen antibodies.

BACKGROUND: This study examined the utility of using radiolabeled anticarcinoembryonic antigen (CEA) monoclonal antibodies (MAbs) as a noninvasive imaging method to aid in the selection of patients for reoperation after operation for medullary thyroid carcinoma (MTC). METHODS: Sixteen patients with persistent or recurrent hypercalcitoninemia since operation or MTC, but had negative or equivocal conventional imaging study results, were given 99mTc-, 123I-, or 131I-labeled NP-4 or MN-14 anti-CEA MAbs. Scintigraphic images were then performed to determine detection of tumor lesions. RESULTS: The MAb scans were positive in 13 (81%) of the 16 patients studied. However, in only three of 13 patients was disease confined to the cervical or mediastinal nodes. In 10 patients, disease was additionally or solely found in distant organs such as liver (five patients), bone (four patients), and periaortic nodes (one patient). On the basis of our studies, only three of the 13 patients with positive scans would benefit from repeat neck exploration, another three would possibly benefit from neck or mediastinal exploration and hepatic resection, and the remaining seven patients would not benefit from any reoperation with curative intent. CONCLUSIONS: MTC imaging with anti-CEA MAbs could be very useful in determining the ideal candidates for repeat neck exploration.

Adult↗

PubMed1997

Structure determination of N-linked oligosaccharides engineered at the CH1 domain of humanized LL2.

Two humanized antibody mutants, hLL2HCN1 and hLL2HCN5, engineered with CH1 domain-appended carbohydrates (CHOs) were generated to facilitate site-specific conjugation of radionuclides and anti-cancer drugs to antibodies. Such site-specific conjugation may minimize the incidence of immunoreactivity perturbation as is often observed with random conjugation. Since the compositions and structures of CHOs are important in determining the chemistry, efficiency, and extent of conjugation, the sequences of the CH1-appended CHOs were determined by exoglycosidase digestions and fluorophore-assisted CHO electrophoresis (FACE). The CHO species attached at HCN1 and HCN5 sites in hLL2HCN1 and hLL2HCN5, respectively, were distinct from each other, heterogeneous, and extensively processed. All of these CHOs were core-fucosylated complex-type oligosaccharides and contained Gal (galactose) and GlcNAc (N-acetylglucosamine) residues in the outer branches. Some of the outer branches were composed of Gal alpha1-3Galbeta1-4GlcNAc structure, also known as alpha-galactosyl epitope. Most of the CHOs were sialylated. While all HCN1-CHOs were biantennary, the majority of HCN5-CHOs (>60%) were triantennary. The CH1-appended CHOs have favorable structural characteristics suitable for site-specific conjugation. For efficient conjugation of large drug complexes, hLL2HCN5 is preferable to hLL2HCN1 because the attached CHO is larger in size and more remotely positioned from the V region. The effects of the alpha-galactosyl epitope found in these CHOs on the immunological properties of the immunoconjugates as efficient cancer diagnostics and therapeutics are being studied.

Antibodies, Monoclonal↗

PubMed1997

Changes in tumor vascular permeability in response to experimental radioimmunotherapy: a comparative study of 11 xenografts.

Single and fractionated doses of radioimmunotherapy (RAIT) and standard chemotherapy (0.6 mg 5-FU/day and 0.36 leucovorin/day on days 1-5) result in decreases in vascular permeability (VP) in the GW-39 human colonic xenograft. The effect of a single dose of RAIT (MN-14 anticarcinoembryonic antigen, Mu-9 anticolon-specific antigen, PAM-4 anti-MUC-1, RS-7 and RS-11 antiepithelial glycoprotein labeled with 131I) has also been evaluated in 10 other tumors. Fourteen days after a fixed 1,500-cGy dose of RAIT, 3 colonic tumors (LS174T, HT-29 and MOSER) all exhibited decreases in VP (58, 75 and 70%, respectively). Two colonic (LoVo and GS-7) and 1 breast tumor (MDA-468) did not exhibit any change in VP, and 1 lung (CALU-3), 1 cervical (ME-180), 1 pancreatic (CaPan-1) and 1 breast cancer line (ZR-75) exhibited increases in tumor VP (214, 289, 170 and 139%, respectively). The differences in VP response to RAIT do not appear to be related to the type of tumor, the size of tumor or the antigen being targeted by RAIT. The differences in tumor VP response to RAIT are discussed in terms of the ability to achieve significant tumor accretion of a second dose of radioantibody on a multiple-dosing regimen. We have begun to investigate the mechanism(s) which regulate the varying responses of tumor VP to RAIT by assessing the role that nitric oxide plays. Administration of arginine, a substrate for nitric oxide synthase, results in increases in both baseline and RAIT-modified VP in GW-39 and ME-180 tumors.

Animals↗

PubMed1997

Regression of advanced refractory ovarian cancer treated with iodine-131-labeled anti-CEA monoclonal antibody.

Advanced chemotherapy-resistant ovarian cancer has a poor prognosis, thus requiring new therapeutic modalities. A complete clinical remission, using two cycles of 131I-labeled murine MN-14 anti-CEA monoclonal antibody (MAb), given intravenously, is reported in a patient with advanced ovarian cancer refractory to paclitaxel (Taxol) therapy. The patient first received radioimmunotherapy with approximately 74 mCi 131I-MN-14 IgG, followed 4 mo later by a similar dose of radiolabeled MAb. A partial remission was seen by CT 1 mo after the first radioimmunotherapy, and a further objective response was documented after the second radioimmunotherapy. CT scans performed 6 and 11 mo after the second radioimmunotherapy showed stable and minimal residual changes. However, a whole-body PET scan with [18F]fluorodeoxyglucose (FDG-PET) was negative in these regions. The CA-125 also decreased to only 13 U/ml, compared to the baseline value of 7700 U/ml. Based on CT, FDG-PET, serum CA-125 and physical exam, the patient was in complete clinical remission for 8 mo when the CA-125 levels rose. CT also showed a new suspicious lesion, presumably a peritoneal implant. No toxicity was seen after the first injection, and only Grade 1 thrombocytopenia and Grade 2 leukopenia developed after the second injection, both reversing within 6 wk. This is a report of a complete clinical remission with radiolabeled anti-CEA antibodies in a patient with chemotherapy-refractive metastatic ovarian cancer.

Aged↗

PubMed1997

Variables influencing tumor dosimetry in radioimmunotherapy of CEA-expressing cancers with anti-CEA and antimucin monoclonal antibodies.

UNLABELLED: In this study, we examined the factors that may influence tumor dosimetry in the radioimmunotherapy of solid, CEA-expressing cancers. METHODS: Data from 119 tumors in 93 patients with CEA-expressing cancers were analyzed. The patients underwent radioimmunotherapy with the 131I-labeled IgG1 anti-CEA antibodies NP-4 (Ka = 10(8) M-1) or MN-14 (Ka = 10(9) M-1), its humanized form hMN-14, as well as the anticolon-specific antigen-p (CSAp) antibody, Mu-9. For dosimetry, the biodistribution, targeting kinetics and cumulated activity of tumors and organs were determined from planar and SPECT imaging. RESULTS: An inverse logarithmic relationship between tumor size and antibody uptake was found for both anti-CEA antibodies, whereas no such relationship was found for Mu-9. The absolute tumor uptake was identified as the most important factor determining the radiation dose to the tumor (r = 0.9), with the biological half-life of the antibody in the tumor being of secondary importance (r = 0.5). No significant difference in tumor uptake was found between both anti-CEA antibodies, despite their tenfold difference in affinity. At comparable masses, colorectal and medullary thyroid cancers had significantly higher tumor uptakes (p = 0.02), as well as tumor-to-red marrow dose ratios, than other cancer types. The tumor half-lives of the anti-CEA antibodies were significantly lower in colorectal than in all other tumor types (p = 0.01). CONCLUSION: In radioimmunotherapy, tumor uptake appears to be the most important dose-determining factor. Differences in antibody affinity are reflected by differences in the biological half-life, not the absolute uptake. Especially favorable conditions for anti-CEA antibodies seem to prevail in colorectal cancer patients having minimal disease, as well as in medullary thyroid cancer, where cytotoxic tumor doses might be expected. Antimucin antibodies may have a particular advantage in the treatment of patients with larger colorectal tumors.

Adenocarcinoma↗

PubMed1997

99Tcm-LL1: a potential new bone marrow imaging agent.

LL1, a monoclonal antibody (MAb) to HLA Class-II-like antigen (li determinant) on the surface of B-lymphocytes, monocytes and histiocytes, was evaluated as an agent for bone marrow imaging. Six patients with diverse diseases (non-Hodgkin's lymphoma, n = 2; multiple myeloma, n = 1; polycythaemia vera, n = 1; lung cancer, n = 1; breast cancer, n = 1) were given low protein doses (< 1 mg) of 99Tcm (30 mCi) labelled Fab' of LL1. 99Tcm-sulphur colloid (SC) imaging was performed in three patients for comparison. Both planar and single photon emission tomographic images were acquired using Sopha gamma cameras. As early as 2 h post-MAb injection, excellent bone marrow images were achieved in all patients, demonstrating both normal or hyperproliferative marrow, as well as 'cold' bone marrow abnormalities such as radiation defects or cancer metastases. Similar to SC, relatively high uptake of LL1 was found in the liver and spleen. However, the bone marrow-to-liver and -spleen uptake ratios were approximately 19-fold higher (0.75 vs 0.04) and 6-fold higher (1.23 vs 0.22), respectively, with LL1 than with SC. The higher bone marrow uptake allowed clearly superior visualization of the thoracic spine when compared to SC. The mean T1/2 of blood and whole-body clearance were 0.4 and 66 h, respectively. The highest radiation absorbed doses (in cGy mCi-1) were observed in the spleen (0.47 +/- 0.24), kidneys (0.25 +/- 0.09) and liver (0.14 +/- 0.04). The bone marrow dose was only 0.05 +/- 0.02 cGy mCi-1. These results indicate that bone marrow imaging with 99Tcm-LL1 is feasible, and that LL1 may be a suitable alternative to SC because of better visualization of the lower thoracic spine. Potential applications include the improved detection of bone marrow metastases of solid tumours and the assessment of haematological disorders.

Animals↗

PubMed1997

Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG.

UNLABELLED: The aim of this study was to determine, in a Phase I/II clinical trial, the pharmacokinetics, dosimetry and toxicity, as well as antitumor activity, of the 131I-labeled murine anti-carcinoembryonic antigen (CEA) monoclonal antibody, NP-4 (IgG1 subtype). METHODS: A total of 57 patients with CEA-expressing tumors (29 colorectal, 9 lung, 7 pancreas, 6 breast and 4 medullary thyroid cancer patients), mostly in very advanced stages, were treated. The patients underwent a diagnostic study (1-3 mg of IgG and 8-30 mCi of 131I) to assess tumor targeting and to estimate dosimetry, followed by the therapeutic dose (4-23 mg and 44-268 mCi), based on the radiation dose to the red marrow. Imaging was performed from 4-240 hr postinjection (planar and SPECT). Blood and whole-body clearance were determined; radiation doses were calculated by the Medical Internal Radiation Dose scheme. RESULTS: Red marrow doses ranged from 45 to 706 cGy, and whole-body doses ranged from 31 to 344 cGy. Differences in pharmacokinetics were found between different types of CEA-producing tumors: blood T 1/2 was significantly lower in colorectal cancer when compared to all other tumor types (21.4 +/- 11.1 hr versus 35.8 +/- 13.2 hr, p < 0.01), as was also whole-body t 1/2. Myelotoxicity was dose-limiting, and its severity was related to the types of prior therapy and extent of bone marrow involvement. In patients without prior radiation or chemotherapy, marrow doses as high as 600 cGy were tolerated without evidence of dose-limiting toxicity. No major toxicity to other organs was observed. Tumor doses were inversely related to the tumor mass and ranged between 2 and 218 cGy/mCi. Modest antitumor effects were seen in 12 of 35 assessable patients (1 partial remission, 4 minor/mixed responses and 7 with stabilization of previously rapidly progressing disease). CONCLUSION: These results suggest that prior chemotherapy or external beam radiation is an important risk factor for the development of hematological toxicity in radioimmunotherapy and that higher radiation doses may be delivered to tumors of patients without prior therapy compromising the bone marrow reserve. The different and, in the individual cases, unpredictable clearance rates suggest the necessity of dosimetry-based treatment planning rather than mCi/m2 dosing. Small tumors seem to be more suitable for radioimmunotherapy because of their favorable dosimetry, but to achieve better therapeutic results in patients with bulky disease, the application of higher, potentially myeloablative doses is indicated.

Aged↗

PubMed1997

Cancer imaging with radiolabeled antibodies: new advances with technetium-99m-labeled monoclonal antibody Fab' fragments, especially CEA-Scan and prospects for therapy.

The use of radiolabeled anticancer antibodies to detect cancer sites by external scintigraphy has had a relatively long history. With the advent of monoclonal antibodies (MAbs), which precluded the need for purifying the antibodies by laborious purification steps, there was a surge of interest and efforts to develop these reagents for both imaging and therapy applications (1). Today, many thousands of patients have received different forms and doses of MAbs for various purposes, and four MAb-based products have been licensed for manufacture and sale in the U.S. (2,3). This article describes the most recent MAb product to be approved in the U.S. for colorectal cancer imaging, including discussions of using this agent and its therapeutic counterpart in several cancer types.

Antibodies, Monoclonal↗

PubMed1996

Antibody penetration of tumor GS-7 xenografts in nude mice: a model for mucinous adenocarcinoma of the colon.

A new cell line derived from a human adenocarcinoma of the colon, GS-7, was propagated as a s.c. tumor in nude mice. This tumor histologically is a mucinous adenocarcinoma (also designated mucoid or colloid) with characteristic large mucin pools that are not lined by an epithelial layer but may contain scattered, randomly distributed cancer cells. Ten to 20% of human colorectal adenocarcinomas are of this histological type, but rapidly growing xenografts with this histology have been rarely used experimentally. This tumor, therefore, constitutes a useful model for similar human tumors. The mucin pools contain large amounts of carcinoembryonic antigen and tumor-associated glycoprotein 72, and the cells express epithelial glycoprotein 2 on their surface. The ability of antibodies injected i.v. to penetrate this tumor was investigated, using both biotinylated and radioiodinated antibodies (Abs). The results demonstrate that Abs can effectively penetrate the mucin pools, and that large amounts of Ab can localize there. This tumor type may have advantages as a target for certain forms of experimental immunotherapy.

Adenocarcinoma, Mucinous↗