The effect of tumor CEA content and tumor size on tissue uptake of indium 111-labeled anti-CEA monoclonal antibody

Philben, Vicki J.; Jakowatz, James G.; Beatty, Barbara; Vlahos, William G.; Paxton, Raymond J.; Williams, Lawrence E.; Shively, John E.; Beatty, J. David

doi:10.1002/1097-0142(19860201)57:3<571::aid-cncr2820570329>3.0.co;2-b

Cited by 66 publications

(18 citation statements)

References 11 publications

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“…In preliminary therapy studies (paper in preparation) we have used doses of conjugate equivalent to 25 units of enzyme activity, which corresponds to 150 ytg of F(ab')2. At this dosage the rate of clearance of conjugated enzyme activity from blood, which tends to be somewhat slower than that reported for unconjugated antibody fragment alone (Rogers et al, 1986;Buchegger et al, 1983), may result from a very low level of circulating CEA ( <Sng ml-'; Philben et al, 1986) in this model. Complexes formed in an antigen excess would tend to be cleared more rapidly from the circulation by the reticulo-endothelial system.…”

Section: Resultssupporting

confidence: 69%

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Inactivation and clearance of an anti-CEA carboxypeptidase G2 conjugate in blood after localisation in a xenograft model

Sharma

Bagshawe²,

Burke³

et al. 1990

Br J Cancer

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Summary Studies with a conjugate of carboxypeptidase G2 (CPG2) and the F(ab')2 fragment of monoclonal anti-CEA antibody, A5B7, have shown specific localisation in a human colon tumour xenograft, LS174T, growing in nude mice. The conjugate reaches a peak concentration in the tumour within 24 h but enzyme activity in blood remains above a critical value for therapeutic purposes for several days. Here we describe a new monoclonal antibody, SB43, raised against CPG2 which is capable of reducing enzyme activity in blood. In vitro studies demonstrated specific binding of SB43 to CPG2 causing inactivation. Moreover, in the nude mouse model SB43 was also capable of inactivating the enzyme in the circulation within minutes of administration. Radiolabelled native SB43 persisted in blood for several days and appreciable non-specific uptake into the xenograft was also observed. Uptake of SB43 by the tumour, with possible inactivation of CPG2 at this site, could be limited by first coupling the antibody to galactose. This ensured recognition and excretion of SB43 and SB43-enzyme complexes via the liver and their rapid removal from the circulation. Galactosylation had no effect on the ability of SB43 to inactivate the enzyme.Anti-cancer agents such as drugs, toxins and radioisotopes have been linked directly to antibodies to achieve greater anti-tumour selectivity but this approach has so far proved to be of restricted therapeutic value. Major limitations resulting from the use of directly coupled antibodies are the amount of anti-cancer agent that can be attached to the antibody molecule without loss of immunological activity and the amount of conjugate that can be specifically targeted to tumour. A novel approach of converting a prodrug into a potent anticancer agent by a targeted enzyme (ADEPT) aims to overcome these difficulties. As originally envisaged (Bagshawe, 1987) this system employed two phases in which an enzyme conjugated to an anti-tumour antibody was first allowed to localise and clear from the circulation before injection of the prodrug. Our preliminary studies (Bagshawe et al., 1988) were carried out with carboxypeptidase G2 (CPG2), a folate depleting bacterial enzyme, conjugated to the F(ab')2 fragment of a monoclonal anti-hCG antibody and capable of converting a glutamyl benzoic acid mustard prodrug into a potent benzoic acid mustard. In the choriocarcinoma xenograft system tested, the target antigen, hCG, was present in the plasma and clearance of the antibody-enzyme conjugate from the circulation occurred within 72 h allowing administration of the prodrug and elimination of the tumour. A similar approach, in which placental alkaline phosphatase was used to convert the prodrug etoposide phosphate into etoposide, was shown to be effective in a colon xenograft model (Senter et al., 1988). We have now extended our studies to the human colonic carcinoma xenograft model (LS174T) in which we have targeted CPG2 conjugated to the monoclonal antibody fragment, A5B7-F(ab')2, directed at carcinoembryonic antigen (CEA...

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Section: Resultssupporting

confidence: 69%

“…This model expresses CEA but the plasma concentration is usually less than 5 ng ml-' for tumours less than 1 g (Philben et al, 1986 …”

Section: Methodsmentioning

confidence: 99%

Inactivation and clearance of an anti-CEA carboxypeptidase G2 conjugate in blood after localisation in a xenograft model

Sharma

Bagshawe²,

Burke³

et al. 1990

Br J Cancer

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“…This finding would suggest that patients with large amounts of circulating immune complexes and small amounts of free radiolabelled antibody have the best uptake of radiolabelled antibody into their tumours. The relationship between the expression of antigen at the tumour cell surface ad the amount shed into the circulation is controversial and is likely to vary from one tumour associated antigen to another (Wagener et al, 1981;Martin & Halpern, 1984;Philben et al, 1986). It is possible that satisfactory antibody imaging may be achieved despite high levels of circulating antigen if the tumour associated antigen is strongly expressed on the cell surface or the affinity of the antibody was greater for the tumour bound antigen than to that in the circulation.…”

Section: Discussionmentioning

confidence: 58%

The effect of circulating antigen and radiolabel stability on the biodistribution of an indium labelled antibody

Davidson

Babich²,

Young³

et al. 1991

Br J Cancer

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Summary This study has investigated two of the main problems with radiolabelled antibody imaging, the formation of circulating immune complexes (I.C.) and the non specific binding of radiolabel to the antibody molecule.Patients undergoing immunoscintigraphy with "'In labelled monoclonal antibody ICR2 were divided into three groups who received either the radiolabelled antibody alone (control, n = 12), the radiolabelled antibody which was incubated with the chelating agent diethylene triamine pentacetic acid (DTPA) prior to size exclusion chromatography (n = 6) or whose injectate was treated with DTPA and cold MAb administered intravenously prior to radiolabelled MAb administration (n = 6). Radiolabelled antibody uptake in abdominal organs was measured by region of interest analysis using a gamma camera with online computer and that in tumour and normal tissues by gamma well counting of biopsies. Circulating antigen and immune complex was measured by high pressure liquid chromatography (HPLC).The sensitivity of tumour imaging and the tumour uptake of radiolabelled antibody was not significantly different between the groups. Patients with high circulating antigen levels developed high levels of circulating immune complex but also had high tumour uptakes of radiolabelled antibody. Administration of cold MAb increased the splenic, but did not effect the tumour uptake of radiolabelled antibody and only minimally reduced levels of circulating immune complex. Chelate administration reduced the urinary excretion of radioactivity but increased the liver uptake of radioactivity.These results have shown that successful antibody imaging can be carried out despite high levels of circulating antigen, that large doses of unlabelled antibody are required to prevent immune complex formation and that removal of non specifically bound "'In does not reduce the liver uptake of radioactivity.

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“…(ii) Higher tumor-to-nontumor ratios are frequently obtained with antibody conjugates than with compounds alone. For example, a tumor-to-blood ratio of 11.9 was measured for an anti-carcinoembryonic antibody monoclonal antibody (14), whereas much lower ratios were observed for several small boron compounds (2,3). (iii) Antihuman tumor antibodies are increasingly available to a wide range of tumors.…”

mentioning

confidence: 99%

Uranium-loaded apoferritin with antibodies attached: molecular design for uranium neutron-capture therapy.

Hainfeld

1992

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

115

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A method is described to deliver 2MU to tumors; the isotope would then be fissioned by incident neutrons, producing localized lethal radiation sufficient for therapy. Apoferritin was loaded with an average of =400 2mU atoms per molecule. Stability of the loaded apoferritin in solution was improved, so that only 8% loss of uranium occurred after 8 days at pH 7. Fab' antibody fragments were covalently attached to the uranium-loaded apoferritin, and the immunoreactivity of the conjugate was 92% of that for antibody alone. Such bio-uranium constructions should provide significant advantages over boronated antibodies to meet the requirements for clinical neutron-capture therapy.Neutron capture is a promising methodology for cancer therapy. Boron is the usual element used, but a system using uranium, as described here, may have significant advantages. Boron neutron-capture therapy is based upon localizing 10B in a tumor and irradiation with slow neutrons (1). Upon neutron absorption, 10B disintegrates to 7Li and an a particle, and these ionizing particles can kill cells. Three approaches have been used in boron neutron-capture therapy: (i) use of boron compounds that localize in tumors (2); (ii) use ofboron compounds that have specific metabolic uptake in tumor cells (3); and (iii) use of boron coupled to anti-tumor antibodies. Based upon antibody sites per tumor cell (105-106) and the concentration of boron necessary for therapy (>15 ppm), it has been estimated that 41000 boron atoms per antibody are required (4). This result has been difficult to achieve, and although recent progress has been made (5), no in vivo localization of the required amount of 10B has been demonstrated. Studies have shown that solid carcinomas exhibit a heterogeneous pattern of antibody distribution (different amounts of antibodies on different cells), have variable vascularity that could limit antibody uptake (6), and show poor penetration of antibodies beyond a few cell layers (7). Because the a and Li particles have a range ofonly about one cell, delivery of boron may be insufficient to many tumor cells.To circumvent some of the problems with boron, uranium may be used instead; this was proposed some 51 yr ago (8).235U has a neutron fission cross section that is 6.6 times lower than the 10B neutron-capture cross section (Table 1). However, a slow neutron splits the nucleus to two heavy charged ions producing 200 MeV, which is 71.4 times greater than the 10B breakup energy. The fission fragments of 235U have a longer range, giving a volume advantage of -8.4 over 10B.Another factor is the effectiveness of these particles in sterilizing cells. Although the 235U fission fragments deposit an average of -28 times more energy per am (measured in keV/pm or linear energy transfer), their effectiveness is not greater by this factor because at some level a cell is killed; further energy deposition is then of no value. Measurements using heavy-ion accelerators impinging on cells have yielded some data on the effectiveness of high linear energ...

show abstract

The effect of tumor CEA content and tumor size on tissue uptake of indium 111-labeled anti-CEA monoclonal antibody

Cited by 66 publications

References 11 publications

Inactivation and clearance of an anti-CEA carboxypeptidase G2 conjugate in blood after localisation in a xenograft model

Inactivation and clearance of an anti-CEA carboxypeptidase G2 conjugate in blood after localisation in a xenograft model

The effect of circulating antigen and radiolabel stability on the biodistribution of an indium labelled antibody

Uranium-loaded apoferritin with antibodies attached: molecular design for uranium neutron-capture therapy.

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