Search PubMed⌕ Search

Biomedical subjects

L E Williams

Publications and source records attributed to L E Williams.

At least 55 records · Page 3Linked to original sources
PubMed1997

Pharmacokinetic modeling and absorbed dose estimation for chimeric anti-CEA antibody in humans.

UNLABELLED: The objective of this article was to model pharmacokinetic data from clinical diagnostic studies involving the 111In-labeled monoclonal antibody (MAb) chimeric T84.66, against carcinoembryonic antigen. Model-derived results based on the 111In-MAb blood, urine and digital imaging data were used to predict 90Y-MAb absorbed radiation doses and to guide treatment planning for future therapy trials. Fifteen patients with at least one carcinoembryonic antigen-positive lesion were evaluated. We report the kinetic parameter estimates and absorbed 111In-MAb dose and projected 90Y-MAb doses for each patient as well as describe our approach and rationale for modeling an extensive set of pharmacokinetic data. METHODS: The ADAPT II software package was used to create three- and five-compartment models of uptake against time in the patient population. The "best-fit" model was identified using ordinary least squares. Areas under the curve were calculated using the modeled curves and input into MIRDOSE3 to estimate absorbed radiation doses for each patient. RESULTS: A five-compartment model best described the liver, whole body, blood and urine data for a subcohort of nine patients with digital imaging data. A three-compartment model best described the blood and urine data for all 15 clinical patients accrued in the clinical trial. For the subcohort, the largest projected 90Y-MAb doses were delivered to the liver (mean, 24.78 rad/mCi; range, 15.02-37.07 rad/mCi), with red marrow estimates on the order of 3.32 rad/mCi (range, 1.24-5.55) of 90Y. Corresponding estimates for the 111In-MAb were 3.18 (range, 2.09-4.43) and 0.55 (range, 0.34-0.74), respectively. CONCLUSION: The three- and five-compartment models presented here were successfully used to represent the blood, urine and imaging data. This was evidenced by the small standard errors for the kinetic parameter estimates and R2 values close to 1. As planned future therapeutic trials will involve stem cell support to alleviate hematological toxicities, the development of an approach for estimating doses to other major organs is crucial.

Adult↗
PubMed1997

Estimating residence times and their associated errors in patient absorbed-dose calculation.

OBJECTIVE: An approach for estimating organ residence times (tau) and their errors in patient internal emitter radiation dosage calculations has been determined. METHODS: Using a modeling algorithm and its associated parameters, chimeric anti-CEA monoclonal antibody (cT84.66) patient organ uptake data and residence times of source organ activity were calculated. Through the covariance matrix of the model's parameters and subsequent Monte Carlo simulations, errors in organ residence time (gamma tau) also were estimated RESULTS: These relative tau errors were found to be model-dependent; increasing as the number of organs being simultaneously modeled in a set of two patients being considered for 90Y-cT84.66 radioimmunotherapy. CONCLUSION: Use of modeling and Monte Carlo methods provide a general, direct procedure for calculating the degree of accuracy of activity integrals and other mathematical functions of kinetic variables.

Algorithms↗
PubMed1996

Minibody: A novel engineered anti-carcinoembryonic antigen antibody fragment (single-chain Fv-CH3) which exhibits rapid, high-level targeting of xenografts.

A novel engineered antibody fragment (VL-VH-CH3, or "minibody") with bivalent binding to carcinoembryonic antigen (CEA) was produced by genetic fusion of a T84.66 (anti-CEA) single-chain antibody (scFv) to the human IgG1 CH3 domain. Two designs for the connecting peptide were evaluated. In the T84.66/212 LD minibody, a two-amino acid linker (generated by fusion of restriction sites) was used to join VH and CH3. In the T84.66/212 Flex minibody, the human IgG1 hinge plus an additional 10 residues were used as the connecting peptide. Size exclusion chromatography of purified minibodies demonstrated that both proteins had assembled into Mr80,000 dimers as expected. Furthermore, analysis by SDS-PAGE under nonreducing conditions was consistent with disulfide bond formation in the hinge of the T84.66 Flex minibody. Purified minibodies retained high affinity for CEA (KA, 2 x 10(9) M(-1)) and demonstrated bivalent binding to antigen. Tumor targeting properties were evaluated in vivo using athymic mice bearing LS174T human colon carcinoma xenografts. 123I-labeled T84.66 minibodies demonstrated rapid, high tumor uptake, reaching 17% injected dose/gram (%ID/g) for the LD minibody and 33%ID/g for the Flex minibody at 6 h following injection. Radioiodinated minibody also cleared rapidly from the circulation, yielding high tumor:blood uptake ratios: 44.5 at 24 h for the LD minibody and 64.9 at 48 h for the Flex minibody. Rapid localization by the T84.66/212 Flex minibody allowed imaging of xenografts at 4 and 19 h after administration.

Animals↗
PubMed1996

Tumor localization of anti-CEA single-chain Fvs: improved targeting by non-covalent dimers.

BACKGROUND: Genetic engineering can produce novel antibody fragments with improved properties for applications such as tumor targeting in vivo. OBJECTIVES: To produce stable monomeric (27 kDa) and dimeric (55 kDa) forms of a single-chain Fv (scFv) from the anti-carcinoembryonic antigen (anti-CEA) antibody T84.66, and assess the targeting and biodistribution properties in an animal model. STUDY DESIGN: ScFv were constructed with either a 28 or 14 amino acid connecting peptide and expressed by secretion from E. coli. Following affinity purification, proteins were characterized by gel electrophoresis and mass spectrometry. Binding properties were assessed by size exclusion HPLC after incubation with antigen, and affinities determined by surface plasmon resonance. The shorter linker favored formation of dimers (and higher multimers) which showed unusual stability. ScFv were radiolabeled with 125I for tumor targeting and biodistribution studies of monomeric or dimeric forms were conducted in athymic mice bearing LS174T human colorectal carcinoma xenografts. RESULTS: 125I-scFv monomers and dimers targeted exhibited rapid clearance kinetics in tumor-bearing mice. Nevertheless, the anti-CEA scFvs targeted very well to xenografts, leading to high tumor: normal organ ratios (greater than 20:1 at 24 h) for both forms. Tumor localization of the non-covalent dimers was much higher than monomers, reaching 10-15% injected dose per gram at 1 h. CONCLUSION: Non-covalent dimers of scFv (also known as diabodies) are stable, easy to produce and show excellent targeting as compared to monomeric scFv, probably due to increased mass and valency.

Animals↗
PubMed1996

A CT assisted method for absolute quantitation of internal radioactivity.

A method is described for the determination of radioactivity (microCi or MBq) at an organ site within an object or patient. Using both anatomic image data (CT or MRI scans) and planar gamma camera images, activity at depth is determined using a matrix inversion method based on least squares. The result of the inversion analysis was the unknown set of n linear (uniform) activity densities representative of each organ within the phantom or patient. The problem was overdetermined since the number of unknown activity densities (microCi/cm) was much less than the number of analysis points (N) within the nuclear image. This method, defined as the CT assisted matrix inversion (CAMI) technique, was accurate to within 15% for a three "organ" plastic phantom, wherein the organs were right circular cylinders having activities of 74 to 508 microCi (or 2.74 MBq to 18.8 MBq). This accuracy included image quantitation effects, particularly assumptions concerning attenuation correction. The average absolute percent error of the estimated activity in four distinct radioactive volumes in the phantom was 9.8%. It was found that the background activity within the phantom was estimated to be too high if sampling regions near strong sources were used in the analysis (scatter effect). This was minimized by going at least 2 cm away from such sources. By applying the method to a monoclonal antibody clinical study, activities within the patient's major organs such as liver, spleen, and kidney could be estimated, even in cases where the organ could not be visualized. Here, the CAMI algorithm gave internally consistent results for the patient's left and right lung linear activity concentrations. The CAMI technique resolves the problem of tissue superimposition using depth information from 3-D CT and is applicable in cases where a number of organs overlap in the gamma camera image. Thus, the method should be generally useful to nuclear image quantitation and the estimation of absorbed radiation doses in patients. One particular application is the estimation of radiation doses in radioimmunotherapy (RIT).

Algorithms↗
PubMed1995

Initial experience evaluating 90yttrium-radiolabeled anti-carcinoembryonic antigen chimeric T84.66 in a phase I radioimmunotherapy trial.

Chimeric T84.66 (cT84.66) is a high-affinity (5 x 10(10) M-1) anti-carcino-embryonic antigen (CEA) IgG1. In a recently completed pretherapy imaging trial, 111In-labeled cT84.66 demonstrated targeting of CEA-producing metastatic sites and low immunogenicity, with human antichimeric antibody (HACA) response in only 1 of 15 patients after a single administration. The purpose of the present study was to evaluate cT84.66-diethylenetriaminepentaacetic acid labeled with 90Y in a dose-escalation Phase I trial. Patients with metastatic CEA-producing malignancies received imaging doses of 5 mCi 111In-labeled cT84.66 first, followed 1-2 weeks later by 5 mg cT84.66 labeled with the therapeutic dose of 90Y. Immediately following the therapeutic infusion, diethylenetriaminepentaacetic acid was administered by continuous i.v. infusion over 3 days at 250 mg/m2 body surface area/24 h. Biodistribution, tumor targeting, absorbed radiation dose estimates, antibody clearance, and HACA response were evaluated through blood samples, 24-h urine collections, and nuclear images performed at serial time points after infusion. To date, three patients with metastatic colorectal cancer have been evaluated at the first dose level of 5 mCi/m2. No side effects were associated with antibody administration. Localization of the antibody to nonhepatic metastatic sites was observed. Size-exclusion high-performance liquid chromatography demonstrated the formation of CEA:antibody complexes in serum in all three patients. A significant variation among patients in the clearance rate of the antibody and complexes from blood to liver was seen, which resulted in a reciprocal relationship between estimated liver dose and red marrow dose. Patients who demonstrated faster clearance to liver demonstrated greater excretion of a low-molecular-weight metabolite through the urine. Two patients developed HACA response, which persisted at 4 months after therapy. At this first dose level, no tumor responses were seen and reversible grade 1 thrombocytopenia was observed in 2 patients. cT84.66 demonstrated effective localization in CEA-producing tumors. Its low immunogenicity after a single administration makes it attractive for further evaluation as a radioimmunotherapeutic agent. However, further evaluation is needed to determine whether its immunogenicity will remain low after multiple administrations. Additionally, in two of the three patients, we identified rapid clearance of the antibody to the liver. This underscores the need to identify, characterize, and understand further those factors that influence the biodistribution and clearance of anti-CEA antibodies to allow for better selection of patients for therapy and rational planning of radioimmunotherapy.

Carcinoembryonic Antigen↗
PubMed1995

The squirrel monkey as an animal model of pelvic relaxation: an evaluation of a large breeding colony.

OBJECTIVE: Findings of pelvic relaxation have been reported in up to 50% of older adult female squirrel monkeys. To evaluate further the potential use of the squirrel monkey as an animal model of pelvic relaxation, we objectively observed and described the perineal findings of 160 adult females. The aim of this study was to examine the relationship of perineal findings to age and parity, factors thought to predispose women to pelvic relaxation. STUDY DESIGN: The urethra, cervix, and anterior and posterior segments of the vagina were evaluated. The degree of support loss at each site was documented. Genital measurements were obtained by previously reported methods. The findings were tested for association with elements of obstetric history, age, and subspecies. RESULTS: The females represented three subspecies and ranged from 3 to 17 years old with parities of 0 to 10. The proportion of females with normal support was inversely related to increasing parity and age. Although birth weights, frequency of dystocia at term, and requirement for cesarean section did not differ significantly between females with and without evidence of prolapse, animals with multiple sites of prolapse tended to have infants with higher birth weights. Animals without prolapse were significantly younger and less likely to have been delivered of a term infant (p < 0.001). Subspecies differences unrelated to age or parity were found for each of the genital measurements. Differences were also found between animals with normal perineal findings and those with findings of prolapse. Animals with prolapse had shorter perineal bodies (p < 0.001), greater genital hiatal ratios (p < 0.001), and wider genital hiatal measurements (p < 0.001). Females with abnormal pelvic findings were of increased parity (4.0 vs 1.6, p < 0.001) and age (9.4 vs 6.3 years, p < 0.001) compared with those normal pelvic findings. CONCLUSION: Analysis of genital prolapse in a large population of breeding squirrel monkeys demonstrated an association of loss of pelvic support with age and parity. A tendency for loss of support at multiple sites was associated with obstetric complications. These observations support continuing investigation into the nature and cause of spontaneous pelvic relaxation in this species and support the potential use of this nonhuman primate as an animal model.

Age Factors↗
PubMed1995

On the correction for radioactive decay in pharmacokinetic modeling.

The question of how to include radioactive decay during biological modeling with first-order differential equations was considered. Modeling may involve either experimental data y(t) or decay-corrected data z(t) [identical to exp(lambda t)y(t) where lambda is the decay constant] for each compartment. It is sometimes assumed that the latter are solutions to corresponding purely pharmacokinetic models (no decay). We primarily compared the two analyses in the case where the model did not require simultaneous consideration of both labeled and unlabeled material. A general theorem was found which limits the use of decay-corrected data to pharmacokinetic models containing linear, homogeneous differential equations. By way of verification, an example of this model type was analyzed for a chimeric monoclonal antibody biodistribution in man. Even in this case, statistically significant differences between the two solutions showed that one may find different model parameters depending upon which data set (y or z) was analyzed. For other mathematical forms, the analyst must include the physical decay in all relevant compartments. By analyzing an open, quadratic model, effects of not including decay were seen to be maximized if the biological rate constant was > or = lambda, the physical decay constant. Finally, using monoclonal antibody-antigen reactions, similar discrepancies between the z functions and the pharmacokinetic variables were demonstrated. This result was found to persist even if competitive molecules were included. We conclude that decay-corrected data may be shown, but should not be entered into the modeling equations unless the latter are of the linear, homogeneous form.

Antibodies, Monoclonal↗
PubMed1994

A mouse model for calculating cross-organ beta doses from yttrium-90-labeled immunoconjugates.

BACKGROUND: The organs of laboratory mice used in radioimmunotherapy experiments are relatively small compared to the ranges of high-energy yttrium-90 (Y-90) beta particles. Current Medical Internal Radiation Dose (MIRD) dosimetry methods do not account for beta energy that escapes an organ. A dosimetry model was developed to provide more realistic dose estimates for organs in mice who received Y-90-labeled antibodies by accounting for physical and geometric factors, loss of beta dose due to small organ sizes, and cross-organ doses. METHODS: The dimensions, masses, surface areas, and overlapping areas of different organs of 10 athymic nude mice, each weighing approximately 25 g, were measured to form a realistic geometric model. Major organs in this model include the liver, spleen, kidneys, lungs, heart, stomach, small intestine, large intestine, thyroid, pancreas, bone, marrow, and carcass. A subcutaneous tumor mass also was included in the model. By accounting for small organ absorbed fractions and cross-organ beta doses, the MIRD methodology was extended from humans to mice for beta dose calculations. RESULTS: Absorbed fractions of beta energy were calculated using the Berger's point kernels and the electron transport code EGS4. Except for the tumor and carcass, the self-organ absorbed fractions ranged from 15% to 20% in smaller organs (the marrow and thyroid) to 65%-70% in larger organs (the liver and small intestine). Cross-organ absorbed fractions also were calculated from estimates of the overlapping surface areas between organs. CONCLUSION: The mathematic mouse model presented here provides more realistic organ dosimetry of radiolabeled monoclonal antibodies in the nude mouse, which should, in turn, contribute to a better understanding of the correlation of biodistribution study results and organ-tumor toxicity information.

Animals↗
PubMed1994

Application of the cross-organ beta dose method for tissue dosimetry in tumor-bearing mice treated with a 90Y-labeled immunoconjugate.

BACKGROUND: Radioimmunotherapy of nude mice bearing human tumor xenografts using 90Y-labeled monoclonal antibodies has resulted in slower tumor growth, decreased tumor burden, and increased survival times. Dosimetry estimates in the murine model usually were based on biodistribution data and standard Medical Internal Radiation Dose approaches. A new dosimetric model for the mouse that takes into consideration the small dimensions, mass, and proximity of murine organs has been developed based on self-organ absorbed and cross-organ doses. METHODS: Nude mice bearing carcinoembryonic antigen-expressing WiDr human colon cancer xenografts were injected with 240 microCi 90Y-anti-carcinoembryonic-antigen monoclonal antibodies and then killed at 12, 24, 72, 120, and 168 hours. Tumors and major organs were removed, weighed, and counted on a gamma counter. Using the resulting biodistribution data, the radiation doses to tumor and normal organs were calculated using the new dosimetric model for the mouse. RESULTS: Three organs (the liver, kidneys, and large bowel) directly received > 50% of the total absorbed beta dose from radioactivity. Lungs, stomach, and marrow received the highest percentage (70-75%) of the total absorbed dose from adjacent organs. Tumor absorbed dose, estimated with the new dosimetric model, was three times less than that obtained with a MIRD-style calculation without correction for self-absorbed and cross-organ doses. CONCLUSIONS: The new dosimetric model, which accounts more accurately for self-organ absorbed and cross-organ beta dose fraction, allows the calculation of tumor and organ doses in the murine model. Accurate estimation of radiation doses to tumor and critical organs, such as the marrow, spleen and kidneys, is important in determining the efficacy and toxicity of radioimmunotherapy regimens in animals and in subsequent human applications.

Animals↗
PubMed1994

Restoration of oocyte maturational competency during the nonbreeding season with follicle-stimulating hormone stimulation in squirrel monkeys (Saimiri boliviensis boliviensis).

The in vitro maturation potential of oocytes retrieved during the nonbreeding season with or without prior in vivo low-dose FSH stimulation was studied in adult squirrel monkeys (Saimiri boliviensis boliviensis). Additionally, the adequacy of various protein supplements in media used for oocyte maturation was investigated. Ovaries were removed from animals in the nonbreeding season (n = 9) with or without prior treatment with a low dose (1 mg) of FSH for four days before ovariectomy. Minimal estradiol elevation was observed in serum even with stimulation. For oocyte collection, ovaries were placed in warmed 21 mM HEPES-buffered Ham's F-10. Oocytes from unstimulated ovaries were retrieved and cultured (47 of 62 recovered) in bicarbonate-buffered Ham's F-10 medium containing 0.5% BSA as protein supplement. Negligible maturation was observed at 48 h (3 of 47; 6%), and no fertilization was seen after insemination. Immature oocytes from animals stimulated with a low dose of FSH were cultured (69 of 94 recovered). With prior FSH stimulation, oocytes placed in 0.5% BSA medium matured (13 of 24; 54%) and fertilized (7 of 21; 33%) in marked contrast to oocytes from the nonstimulated monkeys. Additionally, 20% monkey serum and 20% human follicular fluid were studied as alternative protein supplements for the FSH-pretreated oocytes; these produced similar maturation rates (10 of 22, 45%; 10 of 23, 43%, respectively) and fertilization rates (8 of 21, 38%; 6 of 21, 29%, respectively). In some cases, 2 pronuclei were observed at 16 h and 4 cells were observed at 40 h. Of those activated, 63% showed cleavage ranging from 2 to 8 cells by 96 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

A method including edge effects for the estimation of radioimmunotherapy absorbed doses in the tumor xenograft model.

The temporal relationship of radiolabeled monoclonal antibody (Mab) uptake to tumor size in a nude mouse human colon cancer xenograft model (LS174T) was evaluated as an aid to developing a method for estimation of radioimmunotherapy absorbed dose. Tumors of heterogeneous size were treated with 4.4 MBq (120 microCi) of 90Y-labeled anti-Carcinoembryonic Antigen Mab (90Y-ZCE025). Regression analysis demonstrated an inverse log-log relationship of antibody uptake (%ID/g) to tumor mass in four time intervals investigated (N > 10 points/interval):12-24 h, 2-3 d, 5-7 d, and 10-14 d. Curves of predicted radionuclide concentration vs time were then constructed for a range of constant tumor sizes. Xenograft radiation dose was obtained by temporal integration of each curve and application of appropriate dose estimation formulas. For each assumed tumor mass, an edge correction for loss of beta energy outside the target volume was applied assuming a spherical tumor shape. Estimated average absorbed doses were found to vary only from 13.8-10.3 Gy for a 20-fold change in tumor sizes (0.1-2.0 g, respectively). Such constancy of dose may explain xenograft stasis observed by our group in earlier experiments at this level of administered 90Y activity.

Animals↗
PubMed1994

Bremsstrahlung radiation dose in yttrium-90 therapy applications.

UNLABELLED: The bremsstrahlung component of the decay scheme of beta emitters has been traditionally ignored in internal dosimetry calculations. METHODS: We have estimated the radiation dose from the bremsstrahlung component of the decay scheme of 90Y as a function of distance from a point source in a liquid medium and to body organs from distributed sources of 90Y in the liver and spleen. RESULTS: These estimates agree with measurements of bremsstrahlung dose measured in a Rando phantom, and give an estimate of the importance of this contribution to the overall dosimetry. CONCLUSIONS: The bremsstrahlung radiation absorbed dose contribution from an organ to itself is very small compared to that from the beta dose, but the contribution to other organs is not always negligible, especially when large amounts of 90Y may be involved, as in therapy applications.

Beta Particles↗
PubMed1993

Comparison of radioimmunotherapy and external beam radiotherapy in colon cancer xenografts.

Radioimmunotherapy and external beam radiotherapy were compared in a nude mouse human colon cancer model. Radioimmunotherapy was delivered by intraperitoneal injection of 90Y-labeled anticarcinoembryonic antigen monoclonal antibody (anti-CEA MAB). Single fraction external beam radiotherapy was delivered using a 60Co teletherapy unit. Control groups received saline, unlabeled anti-CEA monoclonal antibody and labeled nonspecific monoclonal antibody. Subcutaneous CEA-expressing LS174T human colon carcinoma tumors were measured over time. Tumor growth suppression was expressed as delay to reach 2g compared to saline controls. Unlabeled anti-CEA monoclonal antibody and labeled nonspecific monoclonal antibody had no effect. External beam radiotherapy of 300, 600, 1000 and 2000 cGy produced growth delays of 3, 12, 17, and 22 days, respectively. Radioimmunotherapy with 120 microCi, 175 microCi, and 225 microCi resulted in growth delays of 20, 34, and 36 days. Estimated absorbed tumor dose was 1750 cGy in the 120 microCi group. Similar comparisons were done with the more radioresistant WiDr human colon carcinoma cell line. External beam radiotherapy doses of 400, 800, 1200, and 1600 cGy resulted in growth delays of 6, 21, 36 and 48 days, respectively. Radioimmunotherapy of 120 microCi and 175 microCi resulted in growth delays of 9 and 19 days, respectively. The 120 microCi dose delivered an estimated absorbed tumor dose of 1080 cGy to WiDr tumors. In summary, for the radiosensitive LS174T line, radioimmunotherapy produced biologic effects that were comparable to a similar dose of single fraction external beam radiotherapy. For the more radioresistant WiDr tumor, radioimmunotherapy produced a biologic effect which was less than a similar dose of single fraction external beam radiotherapy. These studies suggest that a tumor's response to radioimmunotherapy relative to that of external beam radiotherapy is, in part, dependent on tumor radiosensitivity and repair capacity.

Animals↗
PubMed1993

Uptake of radiolabeled anti-CEA antibodies in human colorectal primary tumors as a function of tumor mass.

An inverse correlation has been demonstrated between tumor uptake (u, in units of % injected dose/kg) of monoclonal antibody (Mab) and tumor mass (m, in units of g) for colorectal carcinoma in a series of 19 consecutive patients. The correlation (rho = -0.510), developed using surgical samples was of the form u = amb and was significant at the 2% level of confidence. All tumors were positive for carcinoembryonic antigen (CEA) and the radiopharmaceutical was an iodine-131 labeled anti-CEA Mab. Such correlations have been predicted earlier from murine and rat tumor uptake data. The slope parameter (b) was -0.362, a number consistent with the previous value (-0.382) found in anti-CEA experiments in mice bearing human xenograft LS174T tumors.

Carcinoembryonic Antigen↗