Biomedical subjects

R T O'Donnell

Publications and source records attributed to R T O'Donnell.

At least 19 recordsLinked to original sources

PubMed2005

Enhancement of the therapeutic index: from nonmyeloablative and myeloablative toward pretargeted radioimmunotherapy for metastatic prostate cancer.

PURPOSE: New strategies that target selected molecular characteristics and result in an effective therapeutic index are needed for metastatic, hormone-refractory prostate cancer. EXPERIMENTAL DESIGN: A series of preclinical and clinical studies were designed to increase the therapeutic index of targeted radiation therapy for prostate cancer. (111)In/90Y-monoclonal antibody (mAb), m170, which targets aberrant sugars on abnormal MUC1, was evaluated in androgen-independent prostate cancer patients to determine the maximum tolerated dose and efficacy of nonmyeloablative radioimmunotherapy and myeloablative combined modality radioimmunotherapy with paclitaxel. To enhance the tumor to liver therapeutic index, a cathepsin degradable mAb linkage ((111)In/90Y-peptide-m170) was used in the myeloablative combined modality radioimmunotherapy protocol. For tumor to marrow therapeutic index improvement in future studies, anti-MUC1 scFvs modules were developed for pretargeted radioimmunotherapy. Anti-MUC1 and anti-DOTA scFvs were conjugated to polyethylene glycol scaffolds tested on DU145 prostate cancer cells and prostate tissue arrays, along with mAbs against MUC1 epitopes. RESULTS: The nonmyeloablative maximum tolerated dose of 90Y-m170 was 0.74 GBq/m2 for patients with not more than 10% axial skeleton involvement. Metastatic prostate cancer was targeted in all 17 patients; mean radiation dose was 10.5 Gy/GBq and pain response occurred in 7 of 13 patients reporting pain. Myeloablative combined modality radioimmunotherapy with 0.4 GBq/m2 of 90Y-peptide-m170 and paclitaxel showed therapeutic effects in 4 of 6 patients and 30% less radiation to the liver per unit of activity. Neutropenia was dose limiting without marrow support and patient eligibility was a major limitation to dose escalation. Hypoglycosylated MUC1 epitopes were shown to be abundant in prostate cancer and to increase with disease grade. Anti-MUC1 scFvs binding to prostate cancer tissue and live cells were developed into di-scFv binding modules. CONCLUSIONS: The therapeutic index enhancement for prostate radioimmunotherapy was achieved in clinical studies by the addition of cathepsin cleavable linkers to 90Y-conjugated mAbs and the use of paclitaxel. However, the need for marrow support in myeloablative combined modality radioimmunotherapy restricted eligible patients. Therefore, modular pretargeted radioimmunotherapy, aiming at improving the tumor to marrow therapeutic index, is being developed.

Antibodies, Monoclonal↗

PubMed2001

Radioimmunotherapy with (111)In/(90)Y-2IT-BAD-m170 for metastatic prostate cancer.

PURPOSE: Over 31,000 Americans die of androgen-independent metastatic prostate cancer each year. New strategies that do not involve hormonal manipulation but instead recognize the biochemical and molecular characteristics of prostate cancer are needed. Radioimmunotherapy (RIT) uses a tumor-specific monoclonal antibody to deliver systemic, targeted radiation to cancer. The objectives of this Phase I study of (111)In-2IT-BAD-m170 (for imaging) and (90)Y-2IT-BAD-m170 (for therapy) were to determine the toxicity and maximum tolerated dose (MTD), the specificity for targeting metastatic prostate cancer, and the efficacy for palliation of pain. EXPERIMENTAL DESIGN: M170 is a mouse monoclonal antibody that targets adenocarcinomas. Patients with adequate renal and liver function, rising prostate-specific antigen, and androgen-independent metastatic prostate cancer were eligible. After estimation of dosimetry and pharmacokinetics with (111)In-2IT-BAD-m170, a single dose of (90)Y-2IT-BAD-m170 (0.185, 0.370, 0.555, or 0.740 GBq/m(2)) was administered to cohorts of three patients. Pain was assessed objectively by questionnaires before and for 8 weeks after RIT; weekly prostate-specific antigen levels were obtained for 2 months after RIT. RESULTS: The MTD of (90)Y-2IT-BAD-m170 was 0.740 GBq/m(2) for patients that had up to 10% of the axial skeleton involved with prostate cancer. Toxicity was almost exclusively confined to reversible myelosuppression. Metastatic prostate cancer was targeted by (111)In-2IT-BAD-m170 in all 17 patients. The mean radiation dose delivered to 39 bone and 18 nodal metastases by (90)Y-2IT-BAD-m170 was 10.5 Gy/GBq (range 2.8-25.1). Thirteen of 17 patients reported pain before (90)Y-2IT-BAD-m170; 7 of these 13 had a partial or complete resolution of pain that lasted an average of 4.3 weeks. CONCLUSIONS: This study determined the MTD of (111)In/(90)Y-2IT-BAD-m170 in patients with metastatic prostate cancer. The drugs were well tolerated, targeted metastases, and temporarily palliated pain.

Adenocarcinoma↗

PubMed2001

Metabolite production in patients with lymphoma after radiometal-labeled antibody administration.

UNLABELLED: Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111In- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-Lym-1 (111In/90Y-2IT-BAD-Lym-1). METHODS: Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111In- and 90Y-2IT-BAD-Lym-1; 111In was used as a surrogate tracer for 90Y, which emits no gamma-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111In in organs and tumors. RESULTS: Metabolites and complexes were observed in the plasma of every patient who received 111In-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111In in the patients' plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of 90Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111In-2IT-BAD-m170, 91% and 94% of 111In in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111In-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111In/90Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. CONCLUSION: Metabolites of 111In/90Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111In/90Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.

Adult↗

PubMed2001

Radiolabeled anti-lymphoma antibodies.

This promises to be an era of remarkable change for patients afflicted with NHL. Although the cause of NHL remains unknown, there is greater understanding of 'these diseases' at the molecular level. Insights into genetic aberrations that interrupt apoptosis or that promote proliferation have profound implications for the future management of NHL (and other malignancies). Ongoing trials of immunotherapy and RIT continue to show excellent response rates in patients with relapsed or refractory NHL and remarkably favorable safety and toxicity profiles. More drug approvals can be anticipated. As antibody engineering progresses, formerly theoretical questions regarding optimized targeting and antibody affinity, take on relevance and practicality [65]. The ability to generate new constructs, such as bivalent antibodies, or fusion proteins incorporating two disparate functional proteins, presents exciting opportunities for radiopharmaceutical development. The role of bifunctional antibodies in tumor targeting is likely to increase in importance, both as a means of targeting, and as a technique for increasing MAb specificity [66,67]. Pretargeting approaches are in development as a way of decreasing the amount of time that the radionuclide circulates in the blood (radiating normal tissues) thereby allowing the administration of higher doses of radionuclide (radioactivity and radiation) [67-69].

Animals↗

PubMed2000

Efficacy and toxicity of radioimmunotherapy with (90)Y-DOTA-peptide-ChL6 for PC3-tumored mice.

BACKGROUND: Radioimmunotherapy (RIT) is a new therapeutic modality capable of systemic delivery of radionuclides specifically to sites of metastatic cancer. The L6 monoclonal antibody has been shown to target prostate cancer in preclinical studies and, along with chimeric L6 (ChL6), has been used for RIT in breast cancer patients. METHODS: Pharmacokinetics, blood counts, body weight, and antitumor activity of RIT with (90)yttrium-((90)Y)-DOTA-peptide-ChL6 (75-260 microCi) were determined in nude mice bearing human prostate cancer (PC3) xenografts. RESULTS: RIT produced durable, dose-dependent antitumor effects with a 100% response rate using 112 microCi and 150 microCi (the maximum tolerated dose) of (90)Y-DOTA-peptide-ChL6. Myelotoxicity was reversible, dose-limiting, and dose-related. RIT was associated with improved survival (P = 0.05). All 5 mice in the 150-microCi group survived the 84-day study period vs. 1/8 (13%) for untreated, tumored control mice. CONCLUSIONS: (90)Y-DOTA-peptide-ChL6 targets PC3 human prostate cancer xenografts in nude mice and has an antitumor effect. These results provide a basis for future RIT trials for patients with metastatic prostate cancer.

Animals↗

PubMed2000

Neovascular targeting with cyclic RGD peptide (cRGDf-ACHA) to enhance delivery of radioimmunotherapy.

Radioimmunotherapy (RIT) has been hampered by delivery of only a small fraction of the administered dose of radiolabeled MAb to tumor. A strategy for creating and controlling tumor vascular permeability would enable more effective RIT. The alpha v beta 3 integrin receptor is an appealing target for strategies designed to enhance permeability of tumor vessels because it is highly and preferentially expressed in most tumors. In human tumor mouse models, apoptosis of neovascular endothelial cells has been demonstrated after treatment with alpha v beta 3 antagonists. Since this apoptotic effect could transiently increase permeability of tumor blood vessels, radiolabeled antibodies (MAb) circulating during this period would have increased access to extravascular tumor. To determine if this hypothesis was correct, a pharmacokinetic study of an immunospecific MAb given after an alpha v beta 3 antagonist was performed in nude mice bearing human breast cancer xenografts. The alpha v beta 3 antagonist, cyclic RGD pentapeptide (c-RGDf-ACHA; cyclo arginine glycine aspartic acid D-phenylalanine -1 amino cyclohexane carboxylic acid), inhibits alpha v beta 3 binding to its vitronectin ligand at nanomolar levels. Cyclic RGD peptide (250 micrograms i.p.) given 1 hour before 111In-ChL6 MAb resulted in a 40-50% increase in tumor uptake (concentration), when compared to the control tumor uptake, of MAb 24 hours after administration. When cyclic RGD peptide was given as a continuous infusion (17.5 micrograms/hr) for 1 or 24 hours before 111In-ChL6, tumor uptake of 111In-ChL6 was increased less, and, these data were not statistically different from the control data. There were no differences for any of the groups in the groups in the concentrations of 111In-ChL6 in normal organs or blood when compared to the control group. The results suggest that cyclic RGD peptide provided a temporary, selective increase in tumor vascular permeability, that allowed a larger fraction of the 111In-ChL6 to accumulate in the tumor.

Adenocarcinoma↗

PubMed2000

Are radiometal-labeled antibodies better than iodine-131-labeled antibodies: comparative pharmacokinetics and dosimetry of copper-67-, iodine-131-, and yttrium-90-labeled Lym-1 antibody in patients with non-Hodgkin's lymphoma.

Radioimmunotherapy using radiolabeled monoclonal antibodies against tumor-associated antigens has been efficacious, particularly in the treatment of radiosensitive malignancies such as lymphoma. Antilymphoma monoclonal antibody Lym-1, labeled with copper-67 ((67)Cu), iodine-131 ((131)I), or yttrium-90 ((90)Y), has been effective salvage therapy for patients with non-Hodgkin's lymphoma. Although (131)I has had the dominant role in radioimmunotherapy thus far, several properties of radiometals are preferable. A total of 70 patients with B-lymphocytic non-Hodgkin's lymphoma were studied using (67)Cu-2IT-BAT-Lym-1, (131)I-Lym-1, or (111)In-2IT-BAD-Lym-1. Because (90)Y does not have good emissions for imaging, indium-111 ((111)In), its analogue, was used as a surrogate to estimate (90)Y-2IT-BAD-Lym-1 pharmacokinetics and radiation dosimetry. Subsets of four patients in each group received (67)Cu- and (131)I-labeled Lym-1 or (111)In- and (131)I-labeled Lym-1, allowing direct comparisons of the radioimmunoconjugates. Sequential blood samples and planar images were used to quantitate radioimmunoconjugate in tissues in order to determine pharmacokinetics and radiation dosimetry. (67)Cu-2IT-BAT-Lym-1 and (90)Y-2IT-BAD-Lym-1 exhibited higher cumulated activity concentrations and radiation absorbed doses per unit of administered radioactivity for tumors than did (131)I-Lym-1. The mean tumor cumulated activity (area under the time-activity curve) concentrations per unit of administered radioactivity for (67)Cu-2IT-BAT-Lym-1, (131)I-Lym-1, and (90)Y-2IT-BAD-Lym-1 were 96.89, 33.96, and 43.42 GBq-s/GBq/g, respectively. The mean tumor radiation doses from (67)Cu-2IT-BAT-Lym-1, (131)I-Lym-1, and (90)Y-2IT-BAD-Lym-1 were 2.5, 1.0, and 6.6 Gy/GBq, respectively, because (90)Y deposits more radiation per unit of administered radioactivity. Per unit of administered radioactivity, radiation doses from (67)Cu-2IT-BAT-Lym-1 and (131)I-Lym-1 to normal tissues were similar except that the liver received a higher dose from (67)Cu-2IT-BAT-Lym-1 than from (131)I-Lym-1; radiation doses to normal tissues from (90)Y-2IT-BAD-Lym-1 were generally higher. Consequently, the therapeutic indices (ratio of radiation doses to tumor and normal tissues) for (67)Cu-2IT-BAT-Lym-1, and less generally for (90)Y-2IT-BAD-Lym-1, were more favorable when compared to those for (131)I-Lym-1. Data from the matched subsets of patients showed similar therapeutic indices to those for the groups of patients. (67)Cu-2IT-BAT-Lym-1 showed more potential than (131)I-Lym-1 or (90)Y-2IT-BAD-Lym-1 for non-Hodgkin's lymphoma radioimmunotherapy.

Adult↗

PubMed2000

Radiation dosimetry for 90Y-2IT-BAD-Lym-1 extrapolated from pharmacokinetics using 111In-2IT-BAD-Lym-1 in patients with non-Hodgkin's lymphoma.

UNLABELLED: Several monoclonal antibodies, including Lym-1, have proven effective for treatment of hematologic malignancies. Lym-1, which preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma (NHL) when labeled with 131. Because radiometal-labeled monoclonal antibodies provide higher tumor radiation doses than corresponding 131I-labeled monoclonal antibodies, the radiation dosimetry of 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyc lododecane-N,N',N",N"'-tetraacetic acid-Lym-1 (90Y-21T-BAD-Lym-1) is of importance because of its potential for radioimmunotherapy. Although 90Y has attractive properties for therapy, its secondary bremsstrahlung is less suitable for imaging and pharmacokinetic studies in patients. Thus, the pharmacokinetic data obtained for 111In-21T-BAD-Lym-1 in patients with NHL were used to calculate dosimetry for 90SY-21T-BAD-Lym-1. METHODS: Thirteen patients with advanced-stage NHLwere given a preload dose of unmodified Lym-1 followed by an imaging dose of 111In-21T-BAD-Lym-1. Sequential imaging and blood and urine samples obtained for up to 10 d after infusion were used to assess pharmacokinetics. Using 111In pharmacokinetic data and 90Y physical constants, radiation dosimetry for 90Y-21T-BAD-Lym-1 was determined. RESULTS: The uptake of 111In-21T-BAD-Lym-1 in tumors was greater than uptakes in the lung and kidney but similar to uptakes in the liver and spleen. The biologic half-time in tumors was greater than in lungs. The mean radiation dose to tumors was 6.57 +/- 3.18 Gy/GBq. The mean tumor-to-marrow (from blood) radiation ratio was 66:1, tumor-to-total body was 13:1, and tumor-to-liver was 1:1. Images of 111In were of excellent quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 3 patients. CONCLUSION: Because of the long residence time of 111In-2IT-BAD-Lym-1 in tumors, high 90Y therapeutic ratios (tumor-to-tissue radiation dose) were achieved for some tissues, but the liver also showed high uptake and retention of the radiometal.

Adult↗

PubMed1999

Transfer of copper from a chelated 67Cu-antibody conjugate to ceruloplasmin in lymphoma patients.

The Lym-1 monoclonal antibody was conjugated with the bifunctional chelating agent 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N ',N'',N'''-tetraacetic acid (BAT), using 2IT as a linker, and radiolabeled with 67Cu to make the radiopharmaceutical, 67Cu-2IT-BAT-Lym-1. Ten patients received a total of 18 doses of 67Cu-2IT-BAT-Lym-1 as targeted, systemic radiotherapy. The beta phase of blood clearance, when corrected for 67Cu decay, was positive or flat, a phenomenon not observed in similar patients treated with 131I-Lym-1. The flat beta phase of blood clearance suggested recycling of 67Cu from 67Cu-2IT-BAT-Lym-1 to another plasma protein. Therefore, the amount of 67Cu transferred from the radiopharmaceutical to CP, Alb, and TF was measured using affinity-purified polyclonal antibodies. The fraction of plasma 67Cu precipitated by anti-human CP increased daily; most blood radioactivity was 67Cu-CP after a median of 4 days (range 2-7 days). The transfer of 67Cu to CP was observed in all patients and was consistent from dose to dose within the same patient. An average of 2.8 +/- 1.5% (range 0.8-7.8%) of the 67Cu dose (%ID) was transferred to CP. The release rate of 67Cu-CP from the liver into the blood was 0.9 +/- 0.4 %ID/day for the first 3 days. The 67Cu-CP effective clearance half-life was 3.7 +/- 0.7 days. Subtraction of the 67Cu-CP activity from the total blood radioactivity yielded a biphasic blood clearance similar to that obtained for patients given 131I-Lym-1. Cu-67-CP increased the AUC for whole blood by 24 +/- 10%. The %ID of 67Cu recycled correlated with GGT, ALT, and alkaline phosphatase levels; r = 0.958 (p < 0.001), 0.857 (p < 0.01), and 0.822 (p < 0.01), respectively. Albumin levels correlated negatively with recycled copper (r = -0.745, p < 0.05). The data suggest that the liver metabolizes 67Cu-2IT-BAT-Lym-1 and recycles a small fraction of the 67Cu, transferring it to CP.

Adult↗

PubMed1999

Preclinical evaluation of chimeric L6 antibody for the treatment of Kaposi's sarcoma with radioimmunotherapy.

L6 is a murine IgG2a monoclonal antibody with panadenocarcinoma reactivity. Chimeric L6 (ChL6), the variable region of murine L6 combined with a human IgG1 constant region, has been used in clinical trials for the delivery of radioimmunotherapy to patients with breast cancer. AIDS-associated Kaposi's sarcoma (KS), a malignancy of vascular endothelium, may be an excellent candidate for systemic radioimmunotherapy because KS is well vascularized and radioresponsive. Because ChL6 has been noted to bind vascular endothelium, our hypothesis was that ChL6 will recognize and bind KS tumors making this a potentially useful antibody for the treatment of KS with radioimmunotherapy. To test this hypothesis, 4 human KS spindle cell cultures established from cutaneous punch biopsy specimens (KS-MR, KS-NO, KS-JD and KS 6-3E) and one well-characterized human KS cell line (KS Y-1) were assessed for L6 immunoreactivity. All 5 cell cultures were L6 positive by immunohistochemistry. KS Y-1 cells grown as nude mouse xenografts were also L6 positive by immunohistochemistry. Competitive binding assays performed on the KS Y-1 and KS 6-3E cell cultures showed high density and high affinity cell binding. Biodistribution experiments performed on nude mice with KS Y-1 xenografts demonstrate tumor targeting by ChL6. These findings indicate that ChL6 may be a useful antibody for the radioimmunotherapy of KS. Future experiments will assess the therapeutic efficacy of radiolabeled ChL6 with and without concurrent systemic radiosensitizing chemotherapy.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Radioimmunotherapy of acquired immunodeficiency syndrome (AIDS) associated lymphoma.

Standard therapy for AIDS associated NHL (AANHL) is toxic and often ineffective. Radioimmunotherapy (RIT) is an appealing alternative to chemotherapy because of the radiosensitivity of NHL and the ability of the Lym-1 monoclonal antibody to target therapeutic irradiation to NHL while relatively sparing normal tissue. A Phase I/II study of 90Y-2IT-BAD-Lym-1 was designed specifically for RIT of AANHL. The first patient has been treated with 15 mCi (7.5 mCi/m2) of 90Y-2IT-BAD-Lym-1, after an imaging dose of 111In-2IT-BAD-Lym-1. Before RIT, AANHL in the maxillary sinus extended into the oral cavity and axillary adenopathy was present. Imaging showed excellent accumulation of 111In-2IT-BAD-Lym-1 in the tumors. Substantial shrinkage of the oral lymphoma was observed 18 hours after the therapy dose of 90Y-2IT-BAD-Lym-1 and axillary adenopathy had disappeared by one week after RIT. Transient Grade IV myelosuppression was the only notable toxicity. Further RIT cycles were precluded by development of an antibody response (HAMA) against Lym-1. This novel preliminary study has shown that Lym-1 can target AANHL and produce significant tumor regression thereby providing encouragement to proceed with additional patients.

Adult↗

PubMed1999

Stability of monoclonal antibodies, Lym-1 and ChL6, and 2IT-BAD-Lym-1 immunoconjugate with ultra freezer storage.

UNLABELLED: Use of a single lot of monoclonal antibody (MoAb) or immunoconjugate for clinical studies provides efficiency of scale and consistent characteristics for MoAb-based pharmaceuticals. Lym-1, an anti-lymphoma mouse IgG2 alpha chimeric L6 (ChL6), an anti-adenocarcinoma mouse IgG2 alpha-human IgG1 chimera, and the immunoconjugate 2IT-BAD-Lym-1 were examined for stability following storage. METHODS: Lym-1, ChL6, and 2IT-BAD-Lym-1 were aliquotted with filtration and stored at -70 degrees C for up to 8.5 years. 2IT-BAD-Lym-1 stored for 6.3 years (lot A) was compared to freshly prepared 2IT-BAD-Lym-1 (lot B). MoAbs were thawed and examined yearly by gel filtration high performance liquid chromatography (HPLC), polyacrylamide gel electrophoresis (PAGE), cellulose acetate electrophoresis (CAE), and Scatchard analysis of antigen binding. 2IT-BAD-Lym-1 was evaluated by HPLC, CAE, and radioimmunoassay. To assure the in vivo significance of the in vitro studies, 2IT-BAD-Lym-1 lots A and B were labeled with 111In and their pharmacokinetics in BALB/c mice were compared. RESULTS: Lym-1 demonstrated stability over 8.5 years, providing the following ranges of data over the interval: 98-100% chemical purity (HPLC), 96-100% monomeric fraction (CAE), 8.18-8.46 antigen binding pKa (Scatchard). Similar results were obtained for ChL6 for 7.4 years. HPLC and PAGE of Lym-1 and ChL6 have not changed from original manufacturer specifications, and both MoAbs remain sterile and apyrogenic. No significant differences between 2IT-BAD-Lym-1 lots A and B were observed by in vitro evaluation or pharmacokinetics in mice. CONCLUSIONS: Lym-1, ChL6, and 2IT-BAD-Lym-1 as manufactured and stored for 8.5, 7.4, and 6.3 years, respectively, demonstrated retention of structural and functional integrity.

Animals↗

PubMed1999

Milestones in the development of Lym-1 therapy.

Lym-1, a monoclonal antibody (MAb) that preferentially targets malignant lymphocytes, has induced therapeutic remissions in patients with advanced non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) when labeled with iodine-131 (131I). Based on the strategy of fractionating the total radiation dose, trials were designed to define the safety, toxicity, and efficacy of a series of doses of 131I-Lym-1 given 2-6 weeks apart. All patients had disease resistant to standard therapy. 131I-Lym-1 was given after unconjugated Lym-1 and the 131I dose was escalated in Phase I-II trials. Therapy proved safe. The dose-limiting toxicity was thrombocytopenia. Nonhematological toxicities did not exceed grade 2 except for infrequent instances of grade 3 hypotension. In a low-dose (LD) trial of 131I-Lym-1, tumor regression occurred in 25 (83%) of 30 patients and 17 (57 %) had durable remissions; 3 of the remissions were complete. In a maximum tolerated dose (MTD) trial of 131I-Lym-1, 10 (71%) of 14 entries that received at least two doses of 131I-Lym-1 therapy and 11 (52%) of 21 total entries had remissions; 7 of the remissions were complete. All 3 entries in the MTD cohort of 100 mCi/m2 [3.7 MBq/m2] of body surface area had durable complete remissions. Therapeutic remission and human anti-mouse antibody (HAMA) after Lym-1 therapy were associated with increased survival that was significant in multivariate analyses. Evidence for an Ab3 idiotypic network with an antibody cytotoxic for Raji human lymphoma was found in the only patient examined in detail thus far; this patient was studied because she had a high titer, HAMA and prolonged survival. In conclusion, 131I-Lym-1 induced durable remissions in patients with chemotherapy-resistant NHL or CLL and was associated with acceptable toxicity. In a subset of the patients, survival was quite prolonged perhaps related to development of Ab3.

Animals↗

PubMed1999

Strategies for developing effective radioimmunotherapy for solid tumors.

Single-agent radioimmunotherapy (RIT) has proven efficacy as a treatment for hematological malignancies, particularly non-Hodgkin's lymphoma. Although promising, RIT has been less effective for solid tumors, in part because they are less radiosensitive. Bone marrow transplantation permits the administration of larger radiopharmaceutical doses, but the results of bone marrow transplantation-supported RIT for solid tumors have been marginal. The purpose of this publication is to provide an overview of promising RIT strategies for solid tumors. It is apparent that combination therapy is required, but optimization of the radiopharmaceutical should be the first step. Metallic radionuclides provide higher tumor radiation doses but not necessarily an improved therapeutic index, that is, the ratio of tumor:normal tissue radiation doses. Biodegradable peptide linkers between the chelated metal and the antibody improve the therapeutic index. Further improvements depend on identification of synergistic therapies which recognize that: (a) continuous, low-dose radionuclide therapy acts through apoptosis; and (b) apoptosis is often blocked because most tumors have ineffective p53 and increased Bcl-2. Taxanes are particularly attractive as synergistic agents for RIT because they induce cell cycle arrest in the radiosensitive G2-M phase and p53-independent apoptosis. Optimal sequence and timing for combined modality RIT are critical to achieve synergy. Data from preclinical and clinical studies will be reviewed to illustrate the potential of these strategies.

Animals↗

PubMed1999

Dosimetry-based therapy in metastatic breast cancer patients using 90Y monoclonal antibody 170H.82 with autologous stem cell support and cyclosporin A.

Radioimmunoconjugates of 170H.82 (m170), a panadenocarcinoma monoclonal antibody, are effective for imaging primary and metastatic breast cancer. To evaluate m170 as a targeting agent for therapy, we developed (111)In- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10 tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-m170 immunoconjugates with 99% purity by molecular sieving and immunoreactivity comparable to unmodified antibody. (111)In-m170 pharmacokinetic studies were performed prior to each therapy to determine the maximum dose of 90Y-m170 that could be administered without exceeding a limit of 800 rad to the liver, lungs, or kidneys or 250 rad to the whole body or bone marrow for each of three cycles of treatment. Peripheral blood stem cells (PBSCs) were harvested and cyclosporin A (5 mg/kg twice daily) was administered as strategies to ameliorate myelosuppression and prevent the development of HAMA, respectively. An (111)In imaging/pharmacokinetic study was performed, and the 90Y dose was calculated and administered. The liver was the 90Y dose-limiting organ. The mean and range of calculated doses (in rad/mCi) for the five patients evaluated were as follows: whole body, 2.3 (2.1-2.4); liver, 17.8 (12.7-22.2); lung, 6.4 (4.8-7.2); kidney, 6.9 (6.3-11.5); marrow, 3.6 (1.9-4.4); and tumors (n = 25), 71.5 (14.1-141.5). Of the three patients treated, with doses of 37, 54, and 57 mCi of 90Y, one had a partial response, one had measurable tumor reduction but less than a partial response, and one had stable disease for more than 1 month. PBSCs prevented prolonged myelosuppression. The therapeutic responses, coupled with an absence, thus far, of significant adverse sequelae, suggest that this dosimetry-based approach combined with PBSCs may lead to effective therapy when higher 90Y doses are reached.

Adult↗

PubMed1999

67Copper-2-iminothiolane-6-[p-(bromoacetamido)benzyl-TETA-Lym-1 for radioimmunotherapy of non-Hodgkin's lymphoma.

Copper-67 (67Cu) has ideal properties for radioimmunotherapy. The 62-h half-life is similar to the residence time of antibodies in tumor, and the therapeutic beta emission of 67Cu is comparable to that of 131I. 67Cu, however, has gamma emissions similar to 99mtechnetium that are favorable for imaging. The macrocyclic chelating agent 1,4,7,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA) binds 67Cu tightly and selectively, facilitating linkage to Lym-1, a mouse monoclonal antibody that preferentially targets malignant lymphocytes. The safety, efficacy, and practicality of 67Cu-2-iminothiolane (2IT)-6-[p-(bromoacetamido)benzyl]-TETA (BAT)-Lym-1 was assessed in this Phase I/II clinical trial for patients with non-Hodgkin's lymphoma (NHL) who had failed standard therapy. Up to four doses of 67Cu-2IT-BAT-Lym-1, 25 or 50-60 mCi/m2/dose (0.93 or 1.85-2.22 GBq/m2/dose, respectively) were administered; the lower dosage was used when NHL was detected in the bone marrow. 67Cu-2IT-BAT-Lym-1 provided good imaging of NHL, had favorable radiation dosimetry, and had a response rate of 58% (7 of 12). Hematological toxicity was dose-limiting, but no significant nonhematological toxicity was observed. The ability to image and treat NHL patients with a single radiopharmaceutical with useful physical properties makes 67Cu-labeled monoclonal antibody an option for future clinical trials, as this study showed that 67Cu-2IT-BAT-Lym-1 was safe, effective, and practical.

Adult↗

PubMed1999

A clinical trial of radioimmunotherapy with 67Cu-2IT-BAT-Lym-1 for non-Hodgkin's lymphoma.

UNLABELLED: Encouraged by the results of 131I-Lym-1 therapy trials for patients with B-cell non-Hodgkin's lymphoma (NHL), this phase I/II clinical trial of 67Cu-2IT-BAT-Lym-1 was conducted in an effort to further improve the therapeutic index of Lym-1-based radioimmunotherapy. Lym-1 is a mouse monoclonal antibody that preferentially targets malignant lymphocytes. 67Cu has beta emissions comparable to those of 131I but has gamma emissions more favorable for imaging. The macrocyclic chelating agent 1,4,7,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid binds 67Cu tightly to form a stable radioimmunoconjugate in vivo. METHODS: All 12 patients had stage III or IV NHL that had not responded to standard therapy; 11 had intermediate- or high-grade NHL. At 4-wk intervals, patients received up to four doses of 67Cu-2IT-BAT-Lym-1, 0.93 or 1.85-2.22 GBq/m2 (25 or 50-60 mCi/m2), with the lower dose used when NHL was detected in the bone marrow. RESULTS: 67Cu-2IT-BAT-Lym-1 provided good imaging of NHL and favorable radiation dosimetry. The mean radiation ratios of tumor to body and tumor to marrow were 28:1 and 15:1, respectively. Tumor-to-lung, -kidney and -liver radiation dose ratios were 7.4:1, 5.3:1 and 2.6: 1, respectively. This 67Cu-2IT-BAT-Lym-1 trial for patients with chemotherapy-resistant NHL had a response rate of 58% (7/12). No significant nonhematologic toxicity was observed. Hematologic toxicity, especially thrombocytopenia, was dose limiting. CONCLUSION: 67Cu remains an option for future clinical trials. This study established 67Cu-2IT-BAT-Lym-1 as a safe, effective treatment for patients with NHL.

Bone Marrow↗

PubMed1999

Practical determination of patient-specific marrow dose using radioactivity concentration in blood and body.

UNLABELLED: Accurate determination of red marrow radiation is important because myelotoxicity is often dose limiting in radioimmunotherapy. The S-value methodology assumes a fixed red marrow mass as defined by the standard Medical Internal Radiation Dose (MIRD) mathematic phantom. Substantial error can be introduced in marrow radiation estimates because red marrow mass varies from patient to patient. In this work we describe a patient-specific marrow dosimetry methodology that does not require an explicit estimate of marrow mass. METHODS: Photon radiation to marrow from all sources can be considered as the total body to marrow. Based on photon radiation from body and electron radiation from blood, a patient-specific marrow dose can be determined by counting blood and total body radioactivity and measuring body weight. RESULTS: The deviation in marrow dose calculation using total body to represent all photon radiation was 3.9% in 66 patients administered 131I-labeled antibodies and was 9.1% in 18 patients administered 67Cu-labeled antibodies. The differences between this patient-specific approach and estimates based on standard anatomy were considerable, ranging from -35% to 88%. The differences were greater when patients' weights differed substantially from the MIRD reference man phantom. CONCLUSION: For radiopharmaceuticals that do not bind marrow, patient-specific marrow dosimetry can be independent of the actual marrow mass of a patient. Patient-specific marrow dosimetry can be determined using radioactivity concentration in blood and body.

Body Weight↗