Biomedical subjects

L A Kroger

Publications and source records attributed to L A Kroger.

At least 37 records · Page 2Linked to original sources

PubMed1998

Yttrium-90-DOTA-peptide-chimeric L6 radioimmunoconjugate: efficacy and toxicity in mice bearing p53 mutant human breast cancer xenografts.

UNLABELLED: The novel radioimmunoconjugate, 90Y-DOTA-peptide-chimeric L6 (ChL6), was designed to reduce radiation to critical normal tissues with an exceptionally stable 90Y chelate moiety and a biodegradable linker. Human breast cancer tumors (HBT 3477) in mice were treated with 90Y-DOTA-peptide-ChL6 to examine the effects of increasing dose on the therapeutic efficacy and toxicity of this new agent. METHODS: Groups of athymic mice bearing HBT 3477 xenografts received 4.1- to 14.1-MBq doses of 90Y-DOTA-peptide-ChL6 intravenously. The lethal dose (LD)(50/30), general well-being (weight loss), hematotoxicity and therapeutic efficacy were studied. RESULTS: The LD(50/30) was 12.8 MBq, which corresponded to doses of 17.9 and 50.9 Gy to the total body and tumor (200 mm3), respectively. Deaths were associated with hematotoxicity; no deaths occurred at doses of 9.6 MBq or less. At sublethal doses, the rate of tumor response (cures +/- complete responses + partial responses) increased with increasing dose: 4.1 MBq, 27%; 5.9 MBq, 41%; 8.5 MBq, 69%; and 9.6 MBq, 79% (maximum tolerated dose, MTD). In mice receiving doses of 4.1-9.6 MBq, 6 of 74 (8%) of tumors were cured. Increasing the 90Y dose led to smaller tumor size at nadir and longer tumor regrowth delay but no increase in cure. Although the HBT 3477 p53 gene was found to be mutant resulting in p53 protein not binding DNA breaks, tumors at MTD demonstrated evidence of apoptosis. CONCLUSION: In the human breast cancer athymic mouse model, 90Y-DOTA-peptide-ChL6 had a high therapeutic index and LD(50/30) leading to a 79% response rate at the MTD. The evidence of apoptosis as a mechanism for this tumor response in p53 mutant breast cancer warrants further studies because these observations are relevant to the treatment of lethal breast cancer.

Adenocarcinoma↗

PubMed1998

Comparison of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide-ChL6, a novel immunoconjugate with catabolizable linker, to 2-iminothiolane-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 in breast cancer xenografts.

Radioimmunotherapy using 131I-ChL6 antibody has shown promise in patients with breast cancer. To enhance this potential, a novel ChL6 immunoconjugate that is catabolizable and tightly binds 90Y and (111)In was developed. The immunoconjugate, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide-ChL6, consists of the macrocyclic chelator DOTA linked to ChL6 by a peptide that is preferentially catabolized in the liver. The pharmacokinetic and dosimetric properties of the radioimmunoconjugates (RICs) (111)In- and 90Y-DOTA-peptide-ChL6 and (111)In- and 90Y-2-iminothiolane (2-IT)-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 were compared in athymic mice bearing HBT3477 human breast cancer xenografts. Each of the RICs was stable in vivo and concentrated well in the xenografts. Liver concentration, cumulative radioactivity (activity over time), and radiation dose of the DOTA-peptide-ChL6 RICs were one-third to one-half of those of the corresponding 2-IT-2-[p(bromoacetamido)benzyl]-DOTA-ChL6 RICs. Indium-111 RICs were imperfect tracers for corresponding 90Y RICs, although their pharmacokinetics and radiation dosimetries were similar. The results of this study were consistent with previously published in vitro data, which indicated that the peptide linker of DOTA-peptide-ChL6 was catabolized by cathepsin B. The cumulative activities and radiation doses to the liver of DOTA-peptide-ChL6 RICs were one-half of those of corresponding RICs with the 2-IT linker. Preliminary data from pilot studies in patients with breast cancer are in accord with these observations. These novel DOTA-peptide RICs seem to have excellent clinical potential for radioimmunotherapy associated with marrow transplantation, for which liver radiation is likely to be dose limiting for 90Y.

Animals↗

PubMed1997

Importance of temporal relationships in combined modality radioimmunotherapy of breast carcinoma.

BACKGROUND: The beneficial effects of radioimmunotherapy (RIT) may result from activation of molecular pathways that lead to programmed cell death (apoptosis). The influences of sequence and timing of 90Y-DOTA-peptide-ChL6 antibody (90Y-ChL6) and anti-epidermal growth factor receptor antibody (ch225) or paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) on efficacy and toxicity were examined. METHODS: Groups of human breast carcinoma (HBT 3477) tumored mice received paclitaxel (300 or 600 microg) or ch225 (70, 150, or 350 microg) at various intervals before or after 90Y-ChL6. Mortality, hematologic toxicity, weight loss, and therapeutic efficacy were evaluated. RESULTS: Mice receiving paclitaxel within 24 hours of 90Y-ChL6 had a 100% response rate; 48% were cured when paclitaxel was given 6 or 24 hours after 90Y-ChL6. When 150 microg ch225 was given 24 hours before 90Y-ChL6, the response and cure rates surpassed those of 90Y-ChL6 alone. Timing of administration was critical, with mortality rates as high as 80% in some groups receiving 350 microg ch225 and 90Y-ChL6. CONCLUSIONS: In this aggressive human breast carcinoma model, combined 90Y-ChL6 and paclitaxel had a high therapeutic index with many cures. Sequence of administration was critical in order for ch225 or paclitaxel, when combined with 90Y-ChL6, to enhance the response rate.

Animals↗

PubMed1997

Increased survival associated with radiolabeled Lym-1 therapy for non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

BACKGROUND: Because most patients with advanced non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) respond to radioimmunotherapy (RIT), the study was designed to evaluate the relationship between response and survival in patients treated with radiolabeled Lym-1. METHODS: Fifty-seven patients with NHL (52) or CLL (5) were treated with radiolabeled Lym-1 antibody between 1985 and 1994. Influence of response to treatment on survival was examined directly and was also adjusted for other factors previously found to be significant predictors of survival. A multivariate model that was based on baseline Karnofsky performance status (KPS) and serum lactic dehydrogenase (LDH) predicted response and survival and was used to define risk groups. Proportional-hazards, Kaplan-Meier, and Landmark models were used to evaluate parameters for their ability to predict outcome. RESULTS: By using a proportional-hazards model with response as a time-dependent variable, overall response (P < 0.001) and complete response (P = 0.006) were predictive of increased survival in univariate analyses. Overall response continued to be significant (P = 0.02) in multivariate analyses, even when risk groups that also predicted survival were included. Median survival of responders was 84 weeks, whereas that of nonresponders was 22 weeks when the Landmark method, based on response status at 16 weeks from start of therapy, was used to generate survival curves. CONCLUSIONS: Response to treatment with radiolabeled Lym-1 was associated with increased survival, even when adjusted for baseline clinical parameters that also predicted for survival. The results provide the first unbiased evidence for survival effects of RIT in patients.

Adult↗

PubMed1997

Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: efficacy and toxicity in breast cancer xenografts.

Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. (90)Y-labeled DOTA-peptide-ChL6 ((90)Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and (90)Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving (90)Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24-72 hours before (90)Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after (90)Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with (90)Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to (90)Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with (90)Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with (90)Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy.

Animals↗

PubMed1997

Treatment-related parameters predicting efficacy of Lym-1 radioimmunotherapy in patients with B-lymphocytic malignancies.

This study was designed to evaluate dosimetric, pharmacokinetic, and other treatment-related parameters as predictors of outcome in patients with advanced B-lymphocytic malignancies. Fifty-seven patients were treated with radiolabeled Lym-1 antibody in early phase trials between 1985 and 1994. Logistic regression and proportional hazards models were used to evaluate treatment parameters for their ability to predict outcome, taking into account patient risk group based on Karnofsky performance status and serum lactic dehydrogenase. The occurrence of a partial or complete response (31 of 57 patients) and development of human antimouse antibody (HAMA) predicted improved survival using a time-dependent proportional hazards model. The final multivariate model for survival with parameters significant at P </= 0.05 included overall response and pretreatment risk group. Although some of the dosimetric and pharmacokinetic parameters were predictive in univariate analyses, only longer half-time of radionuclide in the blood showed any indication of improved prediction beyond that provided by the lactic dehydrogenase/Karnofsky performance status-based risk groups. Splenic volume, splenectomy, and malignant tissue Lym-1 reactivity were not contributory. In this patient group, the effect of radiolabeled Lym-1 treatment as indicated by measurable tumor response was associated with improved survival. Development of HAMA was also associated with improved survival, indicating that concern about HAMA should not preclude exploration of radioimmunotherapy. Although dosimetry has a role in determining safety based on dose to normal organs, when adjusted for baseline clinical features, dosimetric and pharmacokinetic parameters showed limited ability to improve outcome prediction.

Adult↗

PubMed1996

Antibody responses to macrocycles in lymphoma.

UNLABELLED: Metallic radioimmunoconjugates have promise for radioimmunoimaging and therapy. Macrocyclic chelating agents allow formation of stable metallic radioimmunoconjugates but have been reported to be immunogenic. This study assesses human antibody responses in patients that were imaged or treated with radiolabeled Lym-1 containing the macrocyclic chelators 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA) or 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA). METHODS: One to six doses (median 1) and 6 to 285 mg (median 33) 67Cu-2IT-BAT (2-iminothiolane bromoacetamidobenzyl TETA)- or 111In-2IT-BAD (2-iminothiolane bromoacetamidobenzyl DOTA)-Lym-1 were administered to each of 18 patients with lymphocytic malignancies. Solid-phase ELISA, utilizing unchelated Lym-1 or human serum albumin conjugated to DOTA, TETA or 2IT-bromoacetamidobenzyl-ethylenediaminetetraacetic acid (BABE) as coating antigens, was used to characterize antibody responses against 67Cu-2IT-BAT-Lym-1 and 111In-2IT-BAD-Lym-1 by quantitating antibodies against the Lym-1, DOTA, TETA or 2IT moieties, respectively. RESULTS: None of the patients had evidence for serum sickness. No patient that received 111In-2IT-BAD-Lym-1 developed antibodies to Lym-1 or DOTA. Two (15%) of the 13 patients that received 67Cu-2IT-BAT-Lym-1 developed antibodies against both TETA and Lym-1, and an additional patient developed antibodies against Lym-1 only. No patient developed an antibody response solely against the macrocycle, nor did any of the patients generate antibodies against the 2IT molecule. HAMA levels were many times greater in amount than HATA levels even when their relative molecular masses were considered. CONCLUSION: Although macrocycles such as DOTA and TETA, and other chelates, can be haptens and thus potentially immunogenic, our findings do not support the view that macrocycles are more immunogenic than other radiometal chelating agents.

Animals↗

PubMed1995

Prognostic factors for radioimmunotherapy in patients with B-lymphocytic malignancies.

The Ann Arbor staging classification has proven less useful in nonHodgkin's lymphoma, because this malignancy is inherently a multifocal disorder. Since 1985, 57 adult patients with advanced B-lymphocytic malignancies that progressed despite standard therapy entered into one of three different therapy trials using radiolabeled Lym-1 antibody. Tumor regression in 31 (54%) of these patients fulfilled conventional requirements for an oncological response to the therapy. To define the role of radioimmunotherapy in B-lymphocytic malignancies better and to find opportunities for improving its therapeutic efficacy, the records of these patients were reviewed to assess the significance of various parameters as prognostic indicators. Twenty-one pretherapy characteristics were evaluated, including age at diagnosis, age at study entry, sex, Karnofsky performance status, prior chemotherapy and radiation therapy, interval since diagnosis, histology, constitutional B symptoms, extranodal malignancy (excluding marrow), bone marrow malignancy, tumor bulk, and circulating malignant cells; blood tests included lymphocyte, granulocyte, platelet, hematocrit, serum lactate dehydrogenase (LDH), interleukin 2 receptor, and human antimouse antibody levels. In the multivariate analysis, LDH and Karnofsky performance status were the parameters that best predicted survival, complete and partial remission, and time to progression; interleukin 2 receptor and LDH best predicted complete remission. These prognostic factors for radioimmunotherapy outcome are consistent with the pretherapy characteristics observed to be significant for chemotherapy.

Adult↗

PubMed1994

Comparative toxicity studies of yttrium-90 MX-DTPA and 2-IT-BAD conjugated monoclonal antibody (BrE-3).

BACKGROUND: BrE-3 is monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Because of observations in therapeutic trials of yttrium-90 (90Y) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the authors attempted to evaluate the importance of this factor by a comparison of the LD50 in healthy mice treated with 90Y that had been chelated with either of two high affinity chelators, methylbenzyldiethylene-triaminepentaacetic acid (MX-DTPA) or bromoacetamidobenzyl-1,4,7,10-tetraazocyclododecane- N,N',N'',N'''-tetraacetic acid (BAD). METHODS AND RESULTS: Bone marrow hematopoietic toxicity was dose-limiting and the source of death for both chelators. The LD50 for 90Y-BrE-3-MX-DTPA was 220.9 microCi, and that for 90Y-BrE-3-2IT-BAD and was 307.8 microCi. Whole-body autoradiography revealed substantially greater uptake of 90Y in the skeleton when MX-DTPA was used as the chelator. CONCLUSIONS: These observations suggest that 90Y escape to bone is a significant factor in the maximum tolerated dose of radioimmunoconjugate that can be used in therapeutic trials. These results probably underestimate the importance of 90Y escape since 90Y in the skeleton of patients is likely to be more significant than in mice because more of the 90Y energy is absorbed in the marrow of larger species.

Animals↗

PubMed1994

The biologic window for chimeric L6 radioimmunotherapy.

BACKGROUND: There has been little success in using radioimmunotherapy in patients with adenocarcinoma, partly because of the low tumor uptake of the administered monoclonal antibody (MoAb). The authors recently reported therapeutic response in advanced cancer patients who received 131I chimeric-L6 MoAb. The L6 MoAb identifies abundant, nonshed antigen that is expressed in many human carcinomas, including carcinomas of the lung, breast, colon, and ovary. In vitro both mouse L6 (L6) and chimeric L6 (ChL6) mediate complement-dependent tumor cytolysis with human serum, and antibody-dependent tumor cell cytolysis with normal human peripheral blood mononuclear cells. The authors have used L6 or ChL6 for radioimmunotherapy to exploit their biologic activity to create a "therapeutic window" of increased vascular permeability, allowing more 131I MoAb to reach the tumor. A reactive target is present in the vascular endothelium but can be covered by unlabeled L6 or ChL6. METHODS: Nine patients with metastatic breast cancer were treated on a therapy protocol and received imaging and therapy doses of 131I ChL6 on two sequential days at 4 week intervals. During each treatment cycle, serum cytokines, complement, albumin, and 131I ChL6 blood clearance were monitored, peripheral blood mononuclear cell activation was assessed, and tumor uptake and response were documented. RESULTS: After L6 or ChL6 was infused, patients demonstrated immediate serum-complement activation, manifested by rapidly decreasing levels of serum complements 3 and 4. Tumor uptake of the second 131I MoAb (therapeutic) injection, given after the second daily injections of 200 mg MoAb, was usually higher than the tumor uptake of the first 131I MoAb (imaging) dose given after a single 200 mg infusion of MoAb. Although serum complement frequently decreased after the first 50-100 mg dose of L6 or ChL6, elevation of soluble interleukin-2 receptor (IL-2R) in serum was seen only in patients who received 150 mg or more of L6 or ChL6. In the nine treated patients, with only one exception, the higher grade of therapeutic tumor response was seen in patients with a greater increase in IL-2R levels. CONCLUSIONS: The clinical importance of understanding these mechanisms is emphasized by the occurrence of measurable tumor regressions in five of the first nine advanced metastatic breast cancer patients treated in this manner. Absence of pulmonary edema and delayed release of dose-dependent IL-2R suggest that targeting of the pulmonary endothelium by L6 or ChL6 is not the major cause of the observed biologic effects. This unique response of a solid tumor to radioimmunoconjugate therapy may be secondary to both the increased delivery of the radioimmunoconjugate to tumor cells caused by enhanced vascular permeability, and to synergistic effects of radiation and activated effector cell mechanisms.

Adult↗

PubMed1994

Overview of radiation myelotoxicity secondary to radioimmunotherapy using 131I-Lym-1 as a model.

The radiation dose-limiting toxicity from radioimmunotherapy has been myelotoxicity in the absence of bone marrow reconstitution (transplantation). Myelotoxicity can be assessed directly by biopsy examination of the bone marrow and indirectly by peripheral blood counts. In patients with B-cell malignancies, thrombocytopenia has been the initial and most severe manifestation of 131I-Lym-1 radiation toxicity from treatment. Manifestations of myelotoxicity varied greatly among the patients and from one treatment dose to another in the same patient, suggesting that additional factors were present. There was an increased likelihood of Grade 3-4 hematopoietic toxicity after 131I-Lym-1 treatment if the patient had peripheral blood cell abnormalities before undergoing 131I-Lym-1 treatment. Fractionation of the total 131I-Lym-1 dose was associated with less toxicity. In many patients, myelotoxicity could not be explained by marrow radiation dose (0.36 +/- 0.13 rads per administered mCi) from 131I-Lym-1 in the blood and body alone. Bone marrow examination and 131I-Lym-1 imaging usually provided evidence for additional marrow radiation from 131I-Lym-1-targeting of marrow malignancy and also for residual toxic effects from prior treatment in these patients. Immunohistologic and imaging examination of the bone marrow performed with the intended treatment antibody allowed assessment of extent of marrow malignancy and prediction of degree of myelotoxicity from subsequent treatment. Treatment programs (and protocols) for radioimmunotherapy should incorporate these methods into the decision process. Larger amounts of 131I-Lym-1 can be used in patients selected to have relatively normal peripheral blood cell counts and normocellular bone marrows uninvolved by the malignancy. These observations appear to be relevant to the maximum tolerated dose in radioimmunotherapy for other malignancies as well.

Antibodies, Monoclonal↗

PubMed1994

Use of response surface statistical designs to detect effects of biologic response modifiers such as IL-2.

Recently many biologic response modifiers have been discovered or produced, but their effects are incompletely understood. The effects of these agents are complicated by their dependence not merely upon the administered dose, nor even the interval of time between administration and observation of effect, but also because of the cascade of interactions that can be invoked. Conventional experimental designs that test a specific combination looking for statistical significance, and that involve doing a series of studies varying one parameter at a time, are likely to require large numbers of animals or patients to answer the question of possible effect, and have a high likelihood of missing the effect altogether because of not selecting the correct combination of parameter levels. Response surface designs are intended for simultaneous multiparameter evaluation and so are less likely to miss an effect. However, if fixed sample designs are employed, the number of subjects required may still be quite large. Sequential designs based on response surface models have been used in other fields but are only now being applied in the fields of biology and medicine. We have explored the use of these designs to evaluate the potential usefulness of interleukin-2 (IL-2) to increase tumor uptake of subsequently administered antibody in nude mice. We found that these methods enabled us to efficiently determine optimal combinations of dose of IL-2 and interval of time between IL-2 and antibody administration for enhancement. Enhancement of tumor uptake of the antibody by IL-2 was substantial in amount and sufficient to stimulate studies in patients where we will use similar sequential methodology for trial design.

Animals↗

PubMed1993

Radioimmunolocalization of metastatic breast carcinoma using indium-111-methyl benzyl DTPA BrE-3 monoclonal antibody: phase I study.

Pharmacokinetics of radiolabeled BrE3 monoclonal antibody (Mab), reactive against a breast mucin epitope, were assessed in 15 patients with advanced breast cancer. Patients received 5 mCi (185 MBq) of 111In-methyl benzyl isothiocyanate DTPA (MX-DTPA) conjugated BrE-3 Mab intravenously with total antibody doses of 10, 50 or 100 mg. Serial quantitative imaging, blood and urine clearance were obtained to measure pharmacokinetics, assess tumor localization and estimate radiation dose. Organ function was followed to determine toxicity. Mild allergic reactions occurred in four patients. Eighty-six percent of 70 known lesions and 5 unsuspected lesions were detected by antibody imaging. Biexponential modeling of radiolabeled antibody in serum showed a T1/2 alpha = 9.5 +/- 2.7 hr and T1/2 beta = 56 +/- 25.4 hr. Total urinary excretion averaged 35.5% +/- 19.3% injected dose (ID) by Day 8. Quantitative imaging showed that 0.02-2.56% ID localized in tumors. Extrapolating dosimetry from 111In-MX-DTPA-BrE-3 to 90Y-MX-DTPA-BrE-3, we estimate therapeutic radiation doses could be delivered to some tumors with tolerable toxicity.

Breast Neoplasms↗

PubMed1991

Quantitative imaging of mouse L-6 monoclonal antibody in breast cancer patients to develop a therapeutic strategy.

L-6, a mouse IgG2a anti-adenocarcinoma monoclonal antibody (MoAb) with favorable immunopathology and mouse biokinetics, was evaluated for cancer radioimmunotherapy by pharmacokinetic studies in 10 patients with breast cancer. The effect of escalating the preinfused protein dose was studied in two patients at each level, using 50, 100, 150, 200 and 400 mg of unlabeled L-6 prior to a 10 mCi imaging dose of 131I L-6. Quantitative imaging, and blood and urine clearances were obtained. After the 50 mg preinfusion, rapid blood clearance and lung extraction of the radiopharmaceutical occurred immediately post injection. Greater preload amounts of L-6 were associated with an increase in the intercept of the slow phase of the blood clearance from 17 to 22% injected dose (ID) with 50 mg to 70 to 80% ID with 400 mg (P less than 0.01). Lung uptake of the radiopharmaceutical immediately post injection decreased from 15 to 19% ID (50 mg) to 6 to 8% ID (400 mg). Tumors were visualized only after larger L-6 preloads, but in these patients small chest tumors contained 0.6-1.2% ID (0.1% ID/g maximum). This study suggests that L-6 reactive sites that are readily available in the lung can be saturated, so that a subsequent dose of I-131 L-6 is delivered to the tumor. This approach provides a new strategy for developing an effective method for radioimmunotherapy using a MoAb that has some cross-reactivity. Quantitative imaging contributed to detection of the cross-reactivity and the strategy for overcoming it.

Adenocarcinoma↗

PubMedDate not supplied

Influence of a peptide linker on biodistribution and metabolism of antibody-conjugated benzyl-EDTA. Comparison of enzymatic digestion in vitro and in vivo.

Insight into the metabolism of radiolabeled antibodies is important for the design of better radioimaging and therapy agents. To test the effect of linkers that can be cleaved in vivo, we introduced Ala-Leu-Ala-Leu between the antibody Lym-1 and an 111In-labeled benzyl-EDTA. For comparison, we studied a conjugate without the linker. Digestion of the two conjugates in vitro showed that the one with Ala-Leu-Ala-Leu was cleaved rapidly by the liver protease cathepsin B1 (T1/2 approximately 6 h). After 100 h of digestion, reversed-phase HPLC product analysis of the Ala-Leu-Ala-Leu conjugate showed that 48% of the total radioactivity had the same retention time as (p-aminobenzyl)-EDTA(In), and 37% of the total radioactivity had the same retention time as [p-(Ala-Leu-amido)benzyl]-EDTA(In). After 97 h of digestion, the conjugate without the linker had 79% of the radioactivity activity still attached to the protein. We also tested the two conjugates in mice. Ala-Leu-Ala-Leu had only a moderate effect on the whole body and liver clearance in vivo. The excretion of the radioactivity was about 6% per day with the linker and about 3% per day without the linker. HPLC analysis of the urine of a single mouse showed products similar to the in vitro study; 54% of the excreted radioactivity had the same retention time as (p-aminobenzyl)-EDTA(In), while 10% had the retention time of [p-(Ala-Leu-amido)benzyl]-EDTA(In).

Amino Acid Sequence↗

PubMedDate not supplied

Analysis of antiglobulin (HAMA) response in a group of patients with B-lymphocytic malignancies treated with 131I-Lym-1.

Host development of human anti-mouse antibodies (HAMA) in response to administered antibodies has been reported as a problem for antibody imaging and therapy. However, radioimmunotherapy has been shown to be effective in patients with B-cell malignancies because their immunodeficient state precludes or delays development of a HAMA response to mouse antibodies. Baseline HAMA activity was assayed in 60 patients with B-lymphocytic non-Hodgkin's lymphoma or chronic lymphocytic leukemia and sequentially in 43 patients who were subsequently treated with radiolabeled Lym-1 antibody. Pre-existing "HAMA" activity was found in 3 (5%) of the 60 patients screened for treatment consideration. The incidence of development of HAMA in the 43 patients treated with multiple doses of radiolabeled Lym-1 antibody was 12 (28%). There was no evidence for an anaphylactoid or related response in the HAMA positive patients. HAMA activity interrupted therapy in 14% of the patients (6 of 43) but did not preclude therapeutic responses to radiolabeled Lym-1 therapy. Medial survival for the HAMA positive patients was longer (18 months) than for those who did not develop HAMA activity (9 months).

Adult↗

PubMedDate not supplied

Radioimmunotherapy for advanced breast cancer using I-131-ChL6 antibody.

BACKGROUND: The biologically active, antiadenocarcinoma monoclonal antibody chimeric L6 (ChL6) was labeled with 131I and administered in cycles to patients with metastatic breast cancer who had failed standard therapy. The therapeutic potential, tumor targeting and maximum tolerated dose of 131I-ChL6 were studied. METHODS: Ten patients with L6 reactive breast cancer received an imaging dose of 131I-ChL6 followed 24 hours later by a therapy dose of 131I-ChL6 (20-70 mCi/m2). Patients received up to 4 monthly cycles unless they had significant myelosuppression, progression of disease, or a high human anti-mouse antibody titer. In vivo activation of effector cell function, complement levels and cytokine release were studied. RESULTS: All 10 patients had detectable cancer on the imaging study. In 7 patients with superficial cancer, the radiation dose was 120 to 3700 cGy/cycle; 5-30 times higher than the whole body dose. Therapy resulted in minimal acute or subacute toxicity. Dose limiting toxicities were neutropenia and thrombocytopenia. Six of 10 patients had clinically measurable tumor responses; 5 had responses that lasted more than one month (1.5-5 months). The MTD for 131I-ChL6, given in at least two monthly doses, was 60 mCi/m2. CONCLUSION: Objective clinical responses were seen in five of 10 patients treated with 131I-ChL6. The tumor response in heavily pretreated, advanced breast cancer may be related to the combined effects of targeted radiation and the biological activity of L6/ChL6.

Adenocarcinoma↗

PubMedDate not supplied

Maximum tolerated dose of 67Cu-2IT-BAT-LYM-1 for fractionated radioimmunotherapy of non-Hodgkin's lymphoma: a pilot study.

PURPOSE: Lym-1, a monoclonal antibody (MoAb) that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine-131 (131I). Radiometal labeled antibodies provide a higher tumor radiation dose than the corresponding 131I labeled antibodies. Based on the strategy of fractionating the total radiation dose, this study was designed to define the maximum tolerated dose (MTD) of the first 2, of a maximum of 4, doses of 67Cu-2IT-BAT-Lym-1 given 4 weeks apart. Additionally, toxicity, radiation dosimetry and efficacy were assessed. MATERIALS AND METHODS: Patients had Ann Arbor stage IVB NHL, resistant to standard therapy, including multiple chemotherapy regimens. Each dose of 67Cu-2IT-BAT-Lym-1 was given after a preload of unmodified Lym-1. A 10 mCi imaging dose of 67Cu-2IT-BAT-Lym-1 was given in order to assess pharmacokinetics and radiation dosimetry prior to therapy. Based on the MTD for 131I-Lym-1 and comparative dosimetry for 131I-Lym-1 and 67Cu-2IT-BAT-Lym-1, the trial was initiated at 60 millicuries per square meter of body surface area (mCi/m2) in cohorts of 3 patients. RESULTS: A single cohort of patients proved sufficient to define the MTD as 60 mCi/m2 for each of the first 2 doses of 67Cu-2IT-BAT-Lym-1. The dose-limiting toxicities were grade 3-4 thrombocytopenia and neutropenia. Neutropenic sepsis and bleeding did not occur. Mean radiation dose contributed to the bone marrow by 67Cu in the body and blood was 0.2 (range, 0.2 to 0.3) rads/mCi. Copper-67 incorporated into ceruloplasmin contributed 25% of the dose to marrow from blood. Non-hematologic toxicities did not exceed grade 2. The three patients had substantial tumor regression even after imaging doses of 67Cu-2IT-BAT-Lym-1. After therapy, one response was complete with a duration of 12 months. Radiation doses to tumors in this patient varied from 7.0-21.9 rads/mCi or 5420-7000 total rads from the course of therapy. CONCLUSION: 67Cu-2IT-BAT-Lym-1 provided good imaging, favorable radiation dosimetry and a remarkably high therapeutic index (ratio of tumor to marrow radiation doses). The non-myeloablative MTD for each of 2 doses was 60 mCi/m2.

Adult↗