Background Radiolabeled monoclonal antibodies recognizing B-lymphocyte surface antigens represent a potentially effective new therapy for lymphomas. We assessed the biodistribution, toxicity, and efficacy of anti-CD20 (B1 and 1F5) and anti-CD37 (MB-1) antibodies labeled with iodine-131 in 43 patients with B-cell lymphoma in relapse. Methods Sequential biodistribution studies were performed with escalating doses of antibody (0.5, 2.5, and 10 mg per kilogram of body weight) trace-labeled with 5 to 10 mCi of 131I. The doses of radiation absorbed by tumors and normal organs were estimated by serial gamma-camera imaging and tumor biopsies. Patients whose tumors were estimated to receive greater doses of radiation than the liver, lungs, or kidneys (i.e., patients with a favorable biodistribution) were eligible for therapeutic infusion of 131I-labeled antibodies according to a phase 1 dose-escalation protocol. Results Twenty-four patients had a favorable biodistribution, and 19 received therapeutic infusions of ...

https://www.nejm.org/doi/pdf/10.1056/NEJM199310213291702

Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support

A physiologically based pharmacokinetic model to describe the biodistribution of a specific monoclonal antibody IgG1 (ZCE025) and its fragments (F(ab')2 and Fab) and of a nonspecific IgG1 (MOPC21) in normal tissues and a human colon carcinoma xenograft (T380) in nude mice is developed. The model simulates the experimental data on the concentration of these four macromolecules in plasma, urine, heart, lung, liver, kidney, spleen, bone, muscle, skin, GI tract, and tumor. This is the first such model for macromolecules with specific binding. A two-pore formalism for transcapillary solute exchange is used which avoids the oversimplifications of unidirectional transport or a single effective permeability coefficient. Comparison of the model with our biodistribution data shows that: (a) a physiologically based pharmacokinetic model for specific and nonspecific antibodies is able to explain experimental data using as few adjustable parameters as possible; (b) for antibodies and fragments, the tumor itself has no significant influence on the pharmacokinetics in normal tissues; and (c) the two-pore formalism for transcapillary exchange describes the data better than a single-pore model without introducing extra adjustable parameters. Sensitivity analysis shows that the lymph flow rate and transvascular fluid recirculation rate are important parameters for the uptake of antibodies, while for the retention of specific antibodies, extravascular binding is the key parameter. A single-pore model could also obtain a good fit between model and data by adjusting two parameters; however, the estimated permeability was 1000 times higher than with the two-pore model, and the binding affinity was such that approximately five times more material was bound than free in the extravascular space for nonspecific antibody. Setting the binding affinity to zero or reducing the value of the permeability-surface area product did not allow a good fit, even when the lymph flow rate was varied. The present model may be useful in scaling up antibody pharmacokinetics from mouse to man.

https://cancerres.aacrjournals.org/content/canres/54/6/1517.full.pdf

Physiologically Based Pharmacokinetic Model for Specific and Nonspecific Monoclonal Antibodies and Fragments in Normal Tissues and Human Tumor Xenografts in Nude Mice

A strategy for covalent modification of monoclonal antibodies utilizing the oxidized oligosaccharide moieties on the molecule was evaluated and compared to more conventional methods. As judged by quantitative in vitro measurements, a monoclonal antibody conjugate prepared via the oligosaccharides retained the homogeneous antigen binding property and affinity of the unmodified antibody. In contrast, conjugates of the same antibody, modified to the same degree on either lysines or aspartic and glutamic acid side chains, were heterogeneous in their antigen binding and had lowered affinity. In vivo biodistribution and nuclear-imaging experiments were also performed with a second monoclonal antibody and a tumor xenograft model. Antibodies modified on the oligosaccharides with either a peptide labeled with iodine-125 or a diethylenetriaminepentaacetic acid chelate with indium-111 localize into target tumors more efficiently than the same antibody radiolabeled on either tyrosines or lysines. These in vivo results, when compared to those reported in the literature for conventionally modified antibodies, suggest that oligosaccharide modification of monoclonal antibodies is a preferred method of preparing conjugates.

https://www.pnas.org/content/pnas/83/8/2632.full.pdf

Site-specific covalent modification of monoclonal antibodies: in vitro and in vivo evaluations

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

Monoclonal antibody-based therapies of leukemia and lymphoma.

Monoclonal antibodies (MoAbs) against carcinoembryonic antigen were successfully radiolabeled with 111In, and the radiopharmaceutical was characterized in vitro and in normal and tumor-bearing mice. The 111In-MoAb proved to be stable in vitro and in vivo under normal conditions, although instability could be induced in vitro with large quantities of iron-free transferrin. Animal distribution studies with 111In-MoAb demonstrated tumor localization superior to 67Ga and pharmacokinetics that were highly similar to those of endogenously labeled 75Se-MoAb. The 111In-MoAb followed first-order kinetics and fit a two-compartmental model when studied in nude mice bearing human colon tumors known to express carcinoembryonic antigen. Significant quantities of radiolabel appeared in tissues other than tumor, with liver and skin having the highest concentrations. Sufficient tumor/background ratios were formed for scanning purposes. The data indicate that 111In-MoAb may prove to be effective as a radiopharmaceutical for tumor imaging.

https://cancerres.aacrjournals.org/content/canres/43/11/5347.full.pdf

Stability, Characterization, and Kinetics of 111In-labeled Monoclonal Antitumor Antibodies in Normal Animals and Nude Mouse-Human Tumor Models

Studies were performed to determine the effect of tumor size on the incorporation of radiolabeled monoclonal antitumor antibodies (MoAbs) into human tumors growing in nude mice. The colon tumors ranged in size from 0.03-1.6 g, the melanoma from 0.1 to 6.7 g, and the lymphoma from 0.06 to 10.2 g. Indium-111 was primarily used as the radiolabel, however, both 125I and 111In were used as tracers for the MoAb in one experiment. The per g radiopharmaceutical uptake by tumors was inversely proportional to tumor size when tumor specific MoAb was administered. This finding was independent of the radiolabel and was demonstrable when the mice bore two tumors of differing size. When the MoAb was not specific for the tumor, the data were less well defined and a statistically significant correlation with size did not occur. These data are strong evidence for a decrease in per g uptake of labeled tumor specific antibodies as tumors increase in size.

https://jnm.snmjournals.org/content/27/3/422.full.pdf

Tumor Size: Effect on Monoclonal Antibody Uptake in Tumor Models

The distribution and kinetics of six human and one murine monoclonal IgM antibodies (MoAb) were studied in BALB/c mice. Labeling was with /sup 111/In, /sup 75/Se, and /sup 125/I. The monomers and pentamers of certain MoAbs were studied. Human distribution studies were also performed. The serum containing (/sup 111/In)MoAb was obtained from one of the patients 24 hr after administration and injected into mice which were then killed and assayed for /sup 111/In distribution. In general, the (/sup 75/Se) and (/sup 111/In)MoAbs had distribution and kinetic patterns that were similar while the /sup 125/I-labeled MoAbs dehalogenated after 4 hr. Monomers and pentamers had highly similar distributions suggesting that the distribution of IgMs may be based on factors other than molecular size. The murine IgM showed a somewhat different distribution in mice than did human IgMs. Serum from the patient containing (/sup 111/In)MoAb had a distribution in mice similar to that of the patient with high liver and gastrointestinal uptake. The human imaging indicates that it is possible to target tumor with human IgM MoAbs, but significant problems remain in regard to their clinical use.

Distribution of radiolabeled human and mouse monoclonal IgM antibodies in murine models.

https://jnm.snmjournals.org/content/29/10/1688.full.pdf

Distribution of RadiolabeledHuman and Mouse Monoclonal 1gMAntibodies in Murine Models

Studies were performed to determine the effect of the radiolabel and circulating carcinoembryonic antigen (CEA) on the pharmacodynamics of monoclonal anti-CEA antibodies (MoAbs). The studies were performed in normal BALB/c mice and in nude mice bearing human colon tumors. Three different tumors were used, each of which produced CEA levels characteristic of that particular tumor's secretory rate. The CEJ-326 MoAb labeled with either 111In or 125I was used in all studies. Circulating CEA induced the removal of 125I and 111In MoAbs from the vascular compartment. Liver concentrations of 111In increased and 125I levels decreased as the CEA secretory rate of the tumor rose. This indicates that circulating CEA complexes form in the vascular compartment which, in an animal model, are removed by the liver and spleen. This results in decreased tumor uptake of the labeled MoAb. The iodinated MoAb complexes are dehalogenated while the 111In is retained by the liver. This dehalogenation may account for the relatively low liver activity observed in radioimmunoimaging with intact radioiodinated anti-CEA MoAbs, provided the CEA complexes are similarly removed from the vascular compartment by the human liver.

In vivo kinetics of radiolabeled monoclonal anti-CEA antibodies in animal models.

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