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[CANCER RESEARCH (SUPPL.) 52, 2747s-275ls, May 1, 1992] Early Intervention in Cancer Using Monoclonal Antibodies and Other Biological Ligands: Micropharmacology and the "Binding Site Barrier"1 John N. Weinstein2 and William van Osdol Theoretical Immunology Section, Laboratory of Mathematical Biology, DCBDC, National Cancer Institute, NIH, Bethesda, Maryland 20892 Abstract Monoclonal antibodies and other biological ligands tend to distribute nonuniformly in bulky tumors after systemic administration. In part, that observation reflects intrinsic heterogeneity of the tumor; in part, it represents poor percolation through tumor substance. Theoretical consid erations led us several years ago to formulate the "binding site barrier" hypothesis, the idea that macromolecular ligands could be prevented from penetrating tumors by the very fact of their successful binding to the target receptor. All else being equal, the higher the density of target moieties (e.g., antigens) and the higher the affinity, the greater the barrier. Experimental evidence for this hypothesis remained circumstantial until we recently obtained direct experimental verification in an animal tumor system. As shown by calculations in the present study, metabolism of ligand in free form or once it has bound to the target can also limit dramatically the extent of penetration. The PERC program package, developed to examine these issues in the case of monoclonal antibodies, has now been applied to other types of ligands as well. We speculate that the same microscopic factors have influenced the evolution of biological ligands, such as the autocrine-paracrine and chemotactic factors. Micro- pharmacological issues (binding sites, molecular size, and charge) should be taken into account as we design the next generation of biological ligands for systemic administration. The same issues are, perhaps, even more important with respect to molecular design of biological factors to be secreted by genetically modified cells in the treatment of cancer and in cancer vaccines. Since the PERC calculations and experiments relate to aggregates of tumor cells no more than a few hundred ¿¿in across, the ideas appear relevant to the problems of early detection and intervention. However, barriers associated with organized epithelial cell layers and basement membrane in the case of early carcinomas and carcinomatous change remain to be understood. Introduction After i.v. administration, macromolecular ligands, including antibodies, tend to distribute heterogeneously in bulky tumors. In part, that observation reflects intrinsic heterogeneity within the mass (1-3); in part, it reflects poor penetration from blood vessels or other sources of supply (4-6). But what about micro scopic, prevascular nodules? Can they be considered completely and immediately penetrable? We do not know of any direct evidence but will present here some calculations suggesting that, even at the microscopic level, penetration can be a limiting factor. Of obvious additional relevance is the issue of access from the blood to cancerous or precancerous cells within the epithelium of lung and other organs, but we will not be dealing with that question here. For a number of years, we have been trying to understand the pharmacology of monoclonal antibodies and other biolog ical ligands by splicing together information on their macro scopic and microscopic pharmacokinetics. This work and the relevant literature are reviewed elsewhere (4, 7-10). Here, we will focus on the microscopic issues, considering the global and regional pharmacology as inputs to the microscopic problem. That is, plasma profiles determine what concentration of anti- ' Presented at the NCI Workshop "Investigations! Strategies for Detection and Intervention in Early Lung Cancer," April 21-24, 1991, Annapolis, MD. 2To whom requests for reprints should be addressed. body is available at each point in time to cross the wall of a capillary and percolate through the extravascular space to reach antigens or other targets associated with cancer cells. Before turning to the microscopic pharmacology, however, it may be useful at least to mention regional routes for adminis tering antibodies and other ligands to organs such as the lung. To circumvent the inefficient access afforded by systemic ad ministration, we studied methods for delivering monoclonal antibodies via regional lymphatics to cancerous nodes in ani mals (11) and humans (12, 13). With Mulshine et al. (14), this approach was then adapted to bronchoscopic administration. In dogs it proved technically feasible to localize antigen specif ically in lymph nodes of the lung and mediastinum, but clinical utility has yet to be demonstrated. That approach has led, in turn, to consideration of aerosol delivery for direct access to the luminal surface of the bronchial epithelium. For review of these issues and of the use of monoclonal antibodies in lung cancer, see Mulshine et al. (15, 16). Microvascular Transport The various possible pathways for transcapillary transport have recently been reviewed elsewhere (4). Very briefly, there are four types of blood capillaries, based on the nature of their endothelium and underlying basement membrane: continuous; fenestrated; sinusoidal; and tight. Continuous capillaries are found in connective tissue, skin, muscle, and most other tissues of the body. In continuous endothelia, adjacent cells are ap- posed to form a more or less continuous lining rich in tight junctions and adjacent to a fully formed basement membrane. Fenestrated capillaries are found in the gastrointestinal tract, in many glands, and in the renal glomerulus. Their endothelium contains fenestrae and clefts of about 30 to 80 nm in diameter. Sinusoids, which have clefts characteristically about 100 nm across, are found in the liver, spleen, and bone marrow. Anti bodies can pass freely through such clefts. Cells of tight endo thelium (blood-brain barrier) contain fewer vesicles in their cytoplasm, and their intercellular junctions are closed off by belts of tight junction. Perhaps surprisingly, there is still not general agreement on the mechanism(s) or pathway(s) by which macromolecules such as the immunoglobulins cross the walls of continuous capillaries. Functionally, the transport properties have been interpreted in terms of a "small pore" pathway for molecules less than about 9 nm in diameter and a "large pore" pathway for materials up to about 70 nm (reviewed in Refs. 17 and 18). In vascularized tumors the situation is even more complex (19, 20). Cancers are characterized by poorly regulated growth, and the resulting heterogeneity (17) is expressed in their vas- culature. Defects are observed in the endothelium and basement membranes of a variety of tumors. In regions of neoangioge- nesis (21), there appears to be a window of time during which macromolecules can extravasate more easily than usual. In some tumors there are areas of partially formed endothelium or even blood channels lined by tumor cells, with no endothe- 2747s on June 6, 2020. © 1992 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from
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Page 1: Early Intervention in Cancer Using Monoclonal Antibodies ... · Early Intervention in Cancer Using Monoclonal Antibodies and Other Biological Ligands: Micropharmacology and the "Binding

[CANCER RESEARCH (SUPPL.) 52, 2747s-275ls, May 1, 1992]

Early Intervention in Cancer Using Monoclonal Antibodies and Other BiologicalLigands: Micropharmacology and the "Binding Site Barrier"1

John N. Weinstein2 and William van Osdol

Theoretical Immunology Section, Laboratory of Mathematical Biology, DCBDC, National Cancer Institute, NIH, Bethesda, Maryland 20892

Abstract

Monoclonal antibodies and other biological ligands tend to distributenonuniformly in bulky tumors after systemic administration. In part, thatobservation reflects intrinsic heterogeneity of the tumor; in part, itrepresents poor percolation through tumor substance. Theoretical considerations led us several years ago to formulate the "binding site barrier"

hypothesis, the idea that macromolecular ligands could be prevented frompenetrating tumors by the very fact of their successful binding to thetarget receptor. All else being equal, the higher the density of targetmoieties (e.g., antigens) and the higher the affinity, the greater the barrier.Experimental evidence for this hypothesis remained circumstantial untilwe recently obtained direct experimental verification in an animal tumorsystem. As shown by calculations in the present study, metabolism ofligand in free form or once it has bound to the target can also limitdramatically the extent of penetration. The PERC program package,developed to examine these issues in the case of monoclonal antibodies,has now been applied to other types of ligands as well. We speculate thatthe same microscopic factors have influenced the evolution of biologicalligands, such as the autocrine-paracrine and chemotactic factors. Micro-

pharmacological issues (binding sites, molecular size, and charge) shouldbe taken into account as we design the next generation of biologicalligands for systemic administration. The same issues are, perhaps, evenmore important with respect to molecular design of biological factors tobe secreted by genetically modified cells in the treatment of cancer andin cancer vaccines. Since the PERC calculations and experiments relateto aggregates of tumor cells no more than a few hundred ¿¿inacross, theideas appear relevant to the problems of early detection and intervention.However, barriers associated with organized epithelial cell layers andbasement membrane in the case of early carcinomas and carcinomatouschange remain to be understood.

Introduction

After i.v. administration, macromolecular ligands, includingantibodies, tend to distribute heterogeneously in bulky tumors.In part, that observation reflects intrinsic heterogeneity withinthe mass (1-3); in part, it reflects poor penetration from bloodvessels or other sources of supply (4-6). But what about microscopic, prevascular nodules? Can they be considered completelyand immediately penetrable? We do not know of any directevidence but will present here some calculations suggestingthat, even at the microscopic level, penetration can be a limitingfactor. Of obvious additional relevance is the issue of accessfrom the blood to cancerous or precancerous cells within theepithelium of lung and other organs, but we will not be dealingwith that question here.

For a number of years, we have been trying to understandthe pharmacology of monoclonal antibodies and other biological ligands by splicing together information on their macroscopic and microscopic pharmacokinetics. This work and therelevant literature are reviewed elsewhere (4, 7-10). Here, wewill focus on the microscopic issues, considering the global andregional pharmacology as inputs to the microscopic problem.That is, plasma profiles determine what concentration of anti-

' Presented at the NCI Workshop "Investigations! Strategies for Detectionand Intervention in Early Lung Cancer," April 21-24, 1991, Annapolis, MD.

2To whom requests for reprints should be addressed.

body is available at each point in time to cross the wall of acapillary and percolate through the extravascular space to reachantigens or other targets associated with cancer cells.

Before turning to the microscopic pharmacology, however, itmay be useful at least to mention regional routes for administering antibodies and other ligands to organs such as the lung.To circumvent the inefficient access afforded by systemic administration, we studied methods for delivering monoclonalantibodies via regional lymphatics to cancerous nodes in animals (11) and humans (12, 13). With Mulshine et al. (14), thisapproach was then adapted to bronchoscopic administration.In dogs it proved technically feasible to localize antigen specifically in lymph nodes of the lung and mediastinum, but clinicalutility has yet to be demonstrated. That approach has led, inturn, to consideration of aerosol delivery for direct access tothe luminal surface of the bronchial epithelium. For review ofthese issues and of the use of monoclonal antibodies in lungcancer, see Mulshine et al. (15, 16).

Microvascular Transport

The various possible pathways for transcapillary transporthave recently been reviewed elsewhere (4). Very briefly, thereare four types of blood capillaries, based on the nature of theirendothelium and underlying basement membrane: continuous;fenestrated; sinusoidal; and tight. Continuous capillaries arefound in connective tissue, skin, muscle, and most other tissuesof the body. In continuous endothelia, adjacent cells are ap-

posed to form a more or less continuous lining rich in tightjunctions and adjacent to a fully formed basement membrane.Fenestrated capillaries are found in the gastrointestinal tract,in many glands, and in the renal glomerulus. Their endotheliumcontains fenestrae and clefts of about 30 to 80 nm in diameter.Sinusoids, which have clefts characteristically about 100 nmacross, are found in the liver, spleen, and bone marrow. Antibodies can pass freely through such clefts. Cells of tight endothelium (blood-brain barrier) contain fewer vesicles in theircytoplasm, and their intercellular junctions are closed off bybelts of tight junction. Perhaps surprisingly, there is still notgeneral agreement on the mechanism(s) or pathway(s) by whichmacromolecules such as the immunoglobulins cross the wallsof continuous capillaries. Functionally, the transport propertieshave been interpreted in terms of a "small pore" pathway formolecules less than about 9 nm in diameter and a "large pore"

pathway for materials up to about 70 nm (reviewed in Refs. 17and 18).

In vascularized tumors the situation is even more complex(19, 20). Cancers are characterized by poorly regulated growth,and the resulting heterogeneity (17) is expressed in their vas-culature. Defects are observed in the endothelium and basementmembranes of a variety of tumors. In regions of neoangioge-nesis (21), there appears to be a window of time during whichmacromolecules can extravasate more easily than usual. Insome tumors there are areas of partially formed endotheliumor even blood channels lined by tumor cells, with no endothe-

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Hum at all. These various types of defective vessels occursporadically, both within and between tumors (22). The overallresult is a generally heterogeneous and unpredictable access tothe extracellular space.

Percolation through Interstitial Space

To understand penetration of tumor substance by biologicalligands, one must take into account the stages of tumor growth(10) shown schematically in Fig. \A. (a) The tumor nodule (ortumor spheroid in culture) grows to about 1 mm in diameter.(b) With further growth, cells at the center become progressivelyless healthy, (c) At 1 to 3 mm, growth leads to necrosis in thecenter, caused by poor oxygénationand nutrition, (d) Forgrowth beyond about 3 mm, a new vascular supply is required.Capillary buds recruited from the surrounding tissues (by"neoangiogenesis") permit explosive growth of the tumor (21).

(e) Beyond about 1 cm in diameter, the center of the tumortends to become necrotic, in considerable part because of internal hydrostatic pressure gradients and volume flows generatedby a lack of local lymphatics. Although the tumor recruits ablood vasculature supply, it does not similarly recruit a lymphatic outflow pathway. Lymph capillaries are specialized toscavenge macromolecules from the tissues, filter them throughthe regional lymph nodes, and return them to the blood circulation. This is the predominant pathway by which macromolecules are cleared from normal tissues (23). Since lymphaticcapillaries are absent from tumors, osmotically active moleculesaccumulate and generate high hydrostatic pressures. The highpressures jeopardize oxygénationand nutrition in at least 3ways: by decreasing flow to the local blood vessels; by closingthem off; and by opposing nitration of molecules from thevessels (18). The latter factor has been analyzed in detail byJain and Baxter (24) and by Baxter and Jain (6). These mechanisms appear to impede delivery of an i.v. administered im-munoglobulin to the central region of a solid tumor. In the caseof an early, prevascular aggregate of tumor cells, such aspectsof bulk tumor would not be present to limit penetration bymacromolecules. However, the calculations to be presented nextindicate that access may be a problem nonetheless.

Calculations Predicting a Binding Site Barrier

We consider an early stage of tumor growth, correspondingto a prevascular primary nodule (or micrometastasis) and, therefore, neglect the effect of pressure gradients within the tumor.The question is this: How do various aspects of the systemcontribute to the spatial and temporal distribution of antibodywithin the nodule? We have investigated this in a planar geometry (4,25), in cylindrical cords of tumor cells around centralcapillaries (5), and in spherical nodules (26-28). Without regardto the specific geometry, a major theme is what we have termedthe "binding site barrier," the idea that bindable immunoglob-

ulin (or any other ligand) will be retarded in its diffusion andconvection through the tumor by the very fact of its successfulbinding (4, 25, 26). Nonuniformity of the antibody distributionwill tend to be increased by a high affinity of binding or a highconcentration of antigenic sites. This tendency can be overcomeby increasing the antibody dose, but the price is a reducedspecificity ratio.

To illustrate the analysis that leads to these predictions, wefocus here on the effects of two parameters, the binding affinityand the rate of antibody metabolism. Fig. \B shows schemati-

< 300/jm

ftu

<1cm >1cm

Capillary

LymphCapillary

Fig. 1. Schematic representation of a tumor nodule.. I. tumor growth throughprevascular (top row) and vascular (bottom row) phases. Cells in the center becomeunhealthy and then necrotic as the nodule grows larger than approximately 300firn in diameter. Growth beyond about 1 mm requires recruitment of capillariesfrom the surrounding normal tissue. Our calculations focus on a prevascularnodule of radius (300 um). B, schematic representation of the explicit model usedfor the simulations discussed in the text. The tumor nodule is surrounded bynormal tissue endowed with blood capillaries and lymph capillaries. The tumoris treated as a distributed system; the blood and lymph are treated as kineticsource and sink, respectively; the extravascular normal tissue space is treated asa homogeneous kinetic compartment, r,,. plasma concentration of ligand; c,,concentration of ligand in extracellular space of normal tissue; K, coefficient fortransfer of ligand across blood capillary wall; L, lymphatic efflux of ligand. Fromvan Osdol et al. (28).

cally the system we are modeling: a microscopic prevascularnodule or aggregate of cells surrounded by normal tissue containing blood vessels and lymphatic capillaries (28). Not included, because we lack the necessary information, is any explicit modeling of the sequestration of antigenic cells within anepithelial layer. We can only speculate on the way in whichthese calculations relate to the immediately relevant problemof cancer (e.g., lung cancer) in situ.

Calculations for this spherical geometry were performed ona CRAY Y-MP computer using a program package that weterm PERC (for "percolation"). PERC uses a collocation

method to solve the system of partial and ordinary differentialequations that describe reaction, diffusion, and convection inthe interstitial volume of a tumor. Serum concentration profiles,transcapillary transport, and lymphatic outflow enter the calculations via the boundary conditions. Plausible parameterestimates were obtained from clinical studies, from preclinicalstudies, from the literature on tumor physiology, and fromcalculations based on in vitro antibody binding experiments (4,29). The computer programs, calculations, and choice of param-

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étervalues are described in detail elsewhere (5, 26-28).Fig. 2 illustrates the effect of increasing antibody affinity (K,)

from 10*to 10IOM~'while holding all other parameters constant

at their baseline values. Although much higher antibody concentrations are attained in the outer regions of the nodule by48 h after injection, the nonuniformity of penetration is greatlyincreased as well, so that the interior of the nodule experiencesmarkedly lower antibody concentrations. This small calculationillustrates a larger point, that binding sites can effectivelyprevent uniform distribution of antibody molecules. If the aimof therapy with an antibody-conjugated drug, toxin, or «-emitter were to damage the blood vessels and immediately surrounding cells in a vascularized tumor, poor percolation away fromthe vessels would be an advantage; if, however, the aim were toreach all tumor cells, including those buried inside a nodule ordistant from the vascular supply, poor percolation could be aproblem. The dose of antibody can often be raised high enoughto swamp the "binding site barrier," but, as previously men

tioned, the trade-off is a loss of specificity. In the limit ofindefinitely high dose, specificity would, of course, be abrogatedcompletely.

Although the calculation here relates to a specific geometryand set of parameter-values, the general principles remain quiterobust as those conditions are altered. The results are similarfor PERC calculations on cylindrical and Cartesian geometries.Elsewhere (30), we have defined a range of antibody characteristics that may provide a useful compromise with respect toaffinity, dose, and the other parameters of the system.

Next, we also consider the effect that metabolism of antigen-antibody complexes can have on the total antibody distribution.This is illustrated by Figs. 3 and 4, in which the total (bound +free) antibody concentration and the specificity ratio, respectively, are plotted as functions of radial position and time. The

Ka

no metabolism 6 hour turnover

24 hour turnover

Fig. 3. Concentration of antibody (bound + free) as a function of time anddistance from the center of a 300-nm-diameter nodule of cancer cells after i.v.bolus injection for different rates of antibody metabolism. The three graphsillustrate the effect that metabolism of antigen-antibody complex has on theantibody distribution. Parameter values for the calculations are listed in Tables Iand 2. M Ih. monoclonal antibodies.

109M'' Ka= 109 M'1

6 hour turnover

Fig. 2. Total monoclonal antibody concentration (bound + free) 48 h after i.v.bolus injection as a function of distance from the center of a spherically symmetrical tumor. The three graphs illustrate the effect of the binding affinity onantibody distribution within the tumor. 150 ^m represents the tumor's outer

surface. Values of the other parameters used for these calculations can be foundin Tables 1 and 2. Higher affinity is associated with poor penetration. MAb,monoclonal antibodies.

24 hour turnover

Fig. 4. The specificity ratio as a function of time and distance from the centerof a 300-jim diameter after i.v. bolus injection of a monoclonal antibody. Wehave defined the specificity ratio (SPEC RATIO) here as the quotient of totaltumor antibody concentration and plasma concentration. The three graphs illustrate the effect that metabolism of the antigen-antibody complex has on the ratio.Parameter values for the calculations are listed in Tables I and 2.

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Table I Parameters for the plasma-time course of monoclonal antibody 9.2.27(39) labeled with '"indium after i.v. bolus injection in human subjects

Antibody 9.2.27 is a murine IgG2a directed against a M, 250,000 glycoprotein-proteoglycan on melanoma cells. These parameter values were used in previousmodeling studies, e.g., Refs. 5 and 7.

X, (s-') X,(s-')

0.27 1.9-10-0.73 7.4-10-

°Plasma monoclonal antibody concentration (Cp) = Cp0-(«ie"*'' + aze *J')>

where Cp0 is the initial plasma concentration, r>,is the fraction cleared with timeconstant I \,. and / is the time in seconds after bolus injection. An additional,very fast transient (about 1 s) not shown here was also included for purelytechnical reasons (to match the initial and boundary conditions near time zero).

Table 2 Baseline parameter values used for simulations discussed in the textFor a discussion of the parameter values and their experimental sources, see

van Osdol et al. (28).

Radius of the tumor noduleEffective interstitial diffusion coefficientProduct of capillary permeability and surface

area/g of tissueInterstitial volume efflux/g of tissueRatio of interstitial and plasma volumesMean density of interstitial tissueRate constant for binding of monoclonal anti

body to antigenRate constant for release of monoclonal anti

body from monoclonal antibody-antigencomplex

Initial monoclonal antibody plasma concentration

Initial antigen concentration

ISOBITI1.3 10-'cmVs8-10~"liters/min/g

5.8-10~7liters/min/g

0.17l.Og/cm'IO*4 NT1 s"1

20 nM

specificity ratio is defined here as the ratio of total antibodyconcentration in the tumor to the concurrent antibody concentration in the plasma (other definitions are, of course, in common use). For this particular calculation, the antigen was assumed to be regenerated or recycled quickly. Other assumptionscould be incorporated. The chosen turnover rates (first orderrate constants for disappearance of the complex) dramaticallyreduce the antibody concentration and specificity ratio, particularly in the interior of the nodule, where times long relative tothe turnover time are required for antibody penetration. Thistype of behavior may be especially relevant to the two-stepapproaches currently being considered for tumor imaging.

Discussion

Many of the factors that determine antibody distribution arestill not understood. Empirical data were used to estimate theinput parameter values for the foregoing calculations, but onlyfragmentary experimental information is available to test thepredictions. For present purposes, results from the PERC calculations should be considered principally as an aid to conceptdevelopment; the parameter values selected are plausible, but itis not yet a matter of fitting experimental data explicitly. Overthe last several years, however, a number of experimental studies have demonstrated qualitatively the nonuniformity of antibody distribution (31-37). Recently, we and our collaborators,working with an animal model tumor, have obtained the firstdirect experimental demonstration of the "binding site barrier"effect predicted by our earlier calculations.3

The concepts discussed here apply quite generally to molecules other than monoclonal antibodies. The whole-body phar-

macokinetics, transcapillary transport, percolation, binding kinetics, and cellular metabolism can be specified (and modeledusing PERC) for macromolecular ligands and for low-molecular-weight molecules as well. We have previously speculated

1 M. Juweid et al., manuscript in preparation.

(38) that the same combination of macroscopic and microscopicfactors has influenced the evolution of biological ligands suchas the autocrine-paracrine and chemotactic factors. These pharmacological issues should be taken into account as we designthe next generation of biological ligands for systemic administration and for secretion in the body by genetically modifiedcells. Since the ideas and the calculations apply directly toaggregates of cancer cells no more than a couple of hundredurn in diameter, they would appear to be relevant to the problems of early detection and intervention. However, additionalbarriers associated with organized epithelial cell layers andbasement membrane should also be taken into account explicitly with respect to early carcinomas.

Acknowledgments

We are grateful to Dr. David G. Covell, Dr. John E. Fletcher, andDr. Kenji Fujimori for their past work on the computer programs usedfor these calculations. We thank the National Cancer Institute forcomputing time and staff support at the Advanced Scientific ComputingLaboratory of the Frederick Research Facility.

References

1. Schlom, J., Colcher, D., Hand, P. H., Wunderlich, D., Nuli, M., andTeramoto, Y. A. Antigenic heterogeneity, modulation, and evolution in breastcancer lesions as defined by monoclonal antibodies. In: M. Rich, J. C. Hager,and P. Furmanski (eds.), Understanding Breast Cancer: Clinical and Laboratory Concepts, pp. 315-358. New York: Marcel Dekker, Inc., 1983.

2. Del Vecchio, S., Reynolds, J. C., Carrasquillo, J. A., Blasberg, R. G.,Neumann, R. D., Lotze, M. T., Bryant, G. J., Farkas, R. J., and Larson, S.M. Local distribution and concentration of intravenously injected 1311-9.2.27monoclonal antibody in human malignant melanoma. Cancer Res., 49:2783-2789, 1989.

3. Del Vecchio, S., Reynolds, J. C., Blasberg, R. G., Neumann, R. D., Carrasquillo, J. A., Hellstrom, I., and Larson, S. M. Measurement of local M,97,000 and 250,000 protein antigen concentration in sections of humanmelanoma tumor using in vitro quantitative autoradiography. Cancer Res.,«.-5475-5481,1988.

4. Weinstein, J. N., Eger, R. R., Covell, D. G., Black, C. D. V., Mulshine, J.,Carrasquillo, J. A., Larson, S. M.. and Keenan, A. M. The pharmacology ofmonoclonal antibodies. Ann. NY Acad. Sci., 507: 199-210. 1987.

5. Fujimori, K., Covell, D. C., Fletcher, J. E.. and Weinstein, J. N. Modelinganalysis of the global and microscopic distribution of IgG, M.ib')... and Fabin tumors. Cancer Res., 49: 5656-5663, 1989.

6. Baxter, L. T., and Jain, R. K. Transport of fluid and macromolecules intumors. I. Role of interstitial pressure and convection. Microvasc. Res., 37:77-104, 1989.

7. Eger, R. R., Covell, D. G., Carrasquillo, J. A., Abrams, P. G., Foon, K. A.,Reynolds, J. C., Schroff, R. W., Morgan, A. C., Larson, S. M., and Weinstein,J. N. Kinetic model for the biodistribution of an '"In-labeled monoclonalantibody in humans. Cancer Res.. 47: 3328-3336, 1987.

8. Covell, D. G., Barnet, J., Holten, O. D., Ill, Black, C. D. V., Parker, R. J.,and Weinstein, J. N. Pharmacokinetics of monoclonal immunoglobulin Gì,F(ab')2, and Fab' in mice. Cancer Res., 46: 3969-3978, 1986.

9. Holton, O. D., Ill, Black, C. D. V., Parker, R. J., Covell, D. G., Barbet, J.,Sieber, S. M., Talley, M. J., and Weinstein, J. N. Biodistribution of monoclonal IgG I, F(ab')2. and Fab' in mice after intravenous injection: a comparison between anti-B-cell (anti-LyB8.2) and irrelevant (MOPC-21) antibodies.J. Immunol., 139: 3041-3049, 1987.

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13. Keenan, A. M., Weinslein, J. N., Carrasquillo. J. \.,etal. Immunolymphos-cintigraphy and the dose dependence of In-111-labeled TI01 monoclonalantibody in patients with cutaneous T-cell lymphoma. Cancer Res., 47:6093-6099, 1987.

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15. Mulshine, J. L., Tockman, M. S., and Smart, C. R. Considerations in the

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33. Abrams, P. G., and Oldham. R. K. Monoclonal antibody therapy of solidtumors. In: K. A. Foon and A. C. Morgan, Jr. (eds.), Monoclonal AntibodyTherapy of Human Cancer, pp. 103-120. Boston, MA: Martinus Nijhoff,1985.

34. Jones, P. L., Gallagher. B. M.. and Sands, H. Autoradiographic analysis ofmonoclonal antibody distribution in human colon and breast tumor xeno-grafts. Cancer Immunol. Immunother., 22: 139-143, 1986.

35. Sutherland, R., Buchegger, F., Schreyer, M., Vacca, A., and Mach, J-P.Penetration and binding of radiolabeled anti-carcinoembryonic antigenmonoclonal antibodies and their antigen binding fragments in human colonmulticellular tumor spheroids. Cancer Res.. 47: 1627-1633. 1987.

36. Blasberg, R. G.. Nakagawa, H., Bourdon, M. A., Groothuis. D. R., Patlak,C. S., and Binger, D. D. Regional localization of a glioma-associated antigendefined by monoclonal antibody 81C6 in vivo: kinetics and implications fordiagnosis and therapy. Cancer Res., 47: 4432-4443, 1987.

37. Epenetos, A. A., Snook, D.. Durbin, H., et al. Limitation of radiolabeledmonoclonal antibody for localization of human neoplasms. Cancer Res., 46:3183-3191,1986.

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