The Pharmacology of Monoclonal Antibodiesa

Weinstein, John N.; Eger, R. R.; Covell, David G.; Black, Christopher D. V.; Mulshine, James L.; Carrasquillo, Jorge A.; Larson, Steven M.; Keenan, Andrew M.

doi:10.1111/j.1749-6632.1987.tb45802.x

Cited by 105 publications

(52 citation statements)

References 14 publications

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“…Amount of leakage also depends on vascular surface area, endothelial permeability, driving force for extravasation, and interstitial fluid pressure (9)(10)(11)(12). Dose, plasma kinetics, specific binding to targets, metabolism, extracellular matrix composition, and lymphatic outflow are additional factors that influence movement of extravasated antibodies in tumors (14,15,43). The effect of high affinity binding of antibodies to tumor cell antigens (''binding site barrier'') on antibody movement in tumors has been shown by using mathematical models (44,45).…”

Section: Discussionmentioning

confidence: 99%

“…High interstitial pressure is thought to result from tumor vessel leakiness coupled with impaired fluid clearance due to the absence of functional intratumoral lymphatics and possibly contractile elements in stroma (10,13). Binding to targets also slows antibody transport in tumors (14,15). Nonuniformity of tumor vessel leakiness (16)(17)(18) imparts additional heterogeneity of antibody access to tumor cells (13).…”

Section: Introductionmentioning

confidence: 99%

“…In approaching the problem, we recognized that detection of antibodies in tumors would be influenced by local concentration, which in turn would be influenced by the amount of extravasation, number and distribution of intratumoral binding sites, barriers, and other factors that govern the distribution of extravasated macromolecules (13)(14)(15)27). Considering all these diverse properties, we selected multiple tracers to assess different factors that influence the accumulation and distribution of antibodies in tumors.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Inhibition of Vascular Endothelial Growth Factor Signaling on Distribution of Extravasated Antibodies in Tumors

et al. 2006

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Antibodies and other macromolecular therapeutics can gain access to tumor cells via leaky tumor vessels. Inhibition of vascular endothelial growth factor (VEGF) signaling can reduce the vascularity of tumors and leakiness of surviving vessels, but little is known about how these changes affect the distribution of antibodies within tumors. We addressed this issue by examining the distribution of extravasated antibodies in islet cell tumors of RIP-Tag2 transgenic mice and implanted Lewis lung carcinomas using fluorescence and confocal microscopic imaging. Extravasated nonspecific immunoglobulin G (IgG) and antibodies to fibrin or E-cadherin accumulated in irregular patchy regions of stroma. Fibrin also accumulated in these regions. Anti-E-cadherin antibody, which targets epitopes on tumor cells of RIP-Tag2 adenomas, was the only antibody to achieve detectable levels within tumor cell clusters at 6 hours after i.v. injection. Treatment for 7 days with AG-013736, a potent inhibitor of VEGF signaling, reduced the tumor vascularity by 86%. The overall area density of extravasated IgG/antibodies decreased after treatment but the change was less than the reduction in vascularity and actually increased when expressed per surviving tumor vessel. Accumulation of anti-E-cadherin antibody in tumor cell clusters was similarly affected. The patchy pattern of antibodies in stroma after treatment qualitatively resembled untreated tumors and surprisingly coincided with sleeves of basement membrane left behind after pruning of tumor vessels. Together, the findings suggest that antibody transport increases from surviving tumor vessels after normalization by inhibition of VEGF signaling. Basement membrane sleeves may facilitate this transport. Antibodies preferentially distribute to tumor stroma but also accumulate on tumor cells if binding sites are accessible. (Cancer Res 2006; 66(3): 1434-45)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Inhibition of Vascular Endothelial Growth Factor Signaling on Distribution of Extravasated Antibodies in Tumors

et al. 2006

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“…to detect or treat a solid tumor, they generally distribute nonuniformly in the mass (1)(2)(3)(4)(5)(6)(7)(8). A number of possible reasons, reflecting the heterogeneity seen in almost all characteristics of cancer (9)(10)(11), have been suggested: heterogeneous antigen (Ag) expression within the tumor; heterogeneous blood supply; elevated interstitial pressure; and mechanical barrierse.g., tight junctions between cells (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

Targeting cancer micrometastases with monoclonal antibodies: a binding-site barrier.

Saga

Neumann

Heya

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

162

103

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Monoclonal antibodies penetrate bulky tumors poorly after intravenous administration, in part because of specific binding to the target antigen. Experiments presented here demonstrate an analogous phenomenon in micrometastases; poor antibody penetration, attributable to a "binding-site barrier" phenomenon, can be seen in guinea pig micrometastases as small as 300 ,um in diameter. Increasing the dose of antibody can partially overcome this limitation, but at a cost in specificity. Six and 72 hr after injection, animals were sacrificed by CO2 inhalation. Organs were rapidly removed and weighed, and tissue radioactivity was determined. Lung tissues with metastases were frozen immediately in OCT compound (Tissue-Tek, Miles) and then processed for autoradiography and immunostaining. For high-dose experiments, 1000 ,ug of unlabeled D3 was added to 30 ,ug of labeled D3. Autoradiography and Immunostaining. Serial 20-,um sections were cut from the frozen lung tissues. For autoradiography, sections were placed on SB-5 film (Eastman Kodak) and exposed for 1-4 days. When 125I-labeled BL3 was coinjected with I311-labeled D3, images of the latter were obtained shortly after sacrifice, images of the former after eight 131I half-lives.The avidin-biotin peroxidase complex (ABC) method (29) was used to compare Ab and Ag distribution. Briefly, tissue sections were acetone-fixed for 10 min and incubated with blocking serum for 20 min. To assess Ag expression, sections were incubated with D3 Ab (20 ,ug/ml) for 1 hr at room temperature, biotinylated horse anti-mouse IgG for 45 min, ABC for three 30-min periods, and diaminobenzidine (Vector Laboratories). When injected D3 was assessed, incubation with D3 was omitted. Some sections were also stained for blood vessels by use of polyclonal rabbit anti-factor VIII and an alkaline phosphatase substrate, Vector Red (30). RESULTS AND DISCUSSIONIn this study, we have assessed the distribution of i.v. administered mAbs in experimental guinea pig lung micrometastases. Two weeks after i.v. injection of L10 cells, multiple metastases 100-1000 ,um in diameter could be seen in the lungs of all animals. This model (metastasis of guinea pig cancer in guinea pigs) is in many ways more relevant to the Abbreviations: Ab, antibody; mAb, monoclonal Ab; Ag, antigen.

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“…Unfortunately, such approaches have not become widely adopted as most quantitative measurements of concentration are still measured and interpreted merely in terms of plasma concentrations and total tissue uptake (11,12). This mini-review summarizes a…”

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confidence: 99%

Compartmental Tissue Distribution of Antibody Therapeutics: Experimental Approaches and Interpretations

Boswell¹,

Bumbaca²,

Fielder³

et al. 2012

AAPS J

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Abstract. Monoclonal antibodies have provided many validated and potential new therapeutic candidates for various diseases encompassing the realms of neurology, ophthalmology, immunology, and especially oncology. The mechanism of action for these biological molecules typically involves specific binding to a soluble ligand or cell surface protein in order to block or alter a molecular pathway, induce a desired cellular response, or deplete a target cell. Many antigens reside within the interstitial space, the fluid-filled compartment that lies between the outer endothelial vessel wall and the plasma membranes of cells. This mini-review examines the concepts relevant to the kinetics and behavior of antibodies within the interstitium with a special emphasis on radiometric measurement of quantitative pharmacology. Molecular probes are discussed to outline chemical techniques, selection criteria, data interpretation, and relevance to the study of antibody pharmacokinetics. The importance of studying the tissue uptake of antibodies at a compartmental level is highlighted, including a brief overview of receptor occupancy and its interpretation in radiotracer studies. Experimental methods for measuring the spatial composition of tissues are examined in terms of relative vascular, interstitial, and cellular volumes using solid tumors as a representative example. Experimental methods and physiologically based pharmacokinetic modeling are introduced as distinct approaches to distinguish between free and bound fractions of interstitial antibody. Overall, the review outlines the available methods for pharmacokinetic measurements of antibodies and physiological measurements of the compartments that they occupy, while emphasizing that such approaches may not fully capture the complexities of dynamic, heterogeneous tumors and other tissues.

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The Pharmacology of Monoclonal Antibodiesa

Cited by 105 publications

References 14 publications

Effect of Inhibition of Vascular Endothelial Growth Factor Signaling on Distribution of Extravasated Antibodies in Tumors

Effect of Inhibition of Vascular Endothelial Growth Factor Signaling on Distribution of Extravasated Antibodies in Tumors

Targeting cancer micrometastases with monoclonal antibodies: a binding-site barrier.

Compartmental Tissue Distribution of Antibody Therapeutics: Experimental Approaches and Interpretations

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