The use of monoclonal antibody conjugates for the diagnosis and treatment of cancer

Pietersz, Geoffrey A.; Kanellos, Jerry; Smyth, Mark J.; Zalcberg, John

doi:10.1038/icb.1987.13

Cited by 29 publications

(25 citation statements)

References 48 publications

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“…Our results are similar to those found by McKenzie et al [18], who used a similar sterically blocked whole ricinantibody conjugate for the treatment of tumours in mice. Our immunotoxin showed a longer blood survival in both the distribution and elimination pharmacokinetic phases.…”

Section: Discussionsupporting

confidence: 94%

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Antitumour activity of a sterically blocked ricin immunotoxin on a human colorectal adenocarcinoma grafted subcutaneously in nude mice

Brusa¹,

Dosio²,

Pietribiasi³

et al. 1992

Cancer Immunol Immunother

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We prepared a ricin-antibody conjugate, lacking the ability to bind the galactosidic residues of Sepharose 6B, a so-called blocked immunotoxin. The monoclonal antibody AR-3 was cross-linked to ricin through a thioether bond. Further studies showed that the immunoconjugate suppressed the tumour growth of HT-29 cells in intraperitoneally grafted nude mice, without showing any undesirable ricin toxicity. In this work, to demonstrate the therapeutic activity of the AR-3-ricin conjugate injected into mice bearing subcutaneous tumour, we first evalauted its pharmacokinetic behaviour and biodistribution. The behaviour of the immunoconjugate injected intravenously was almost intermediate between that of the antibody and ricin. Moreover, when the immunotoxin was intravenously administered to nude mice bearing subcutaneous tumour, no therapeutic effects appeared, in accordance with the relatively low permeability of the immunotoxin from the blood to the skin. In contrast, peritumoral treatment produced a strong reduction of the neoplastic nodules without substantial regrowth of the malignant cells. This result was also achieved when the immunotoxin treatment was performed on a well-established tumour. This finding was strictly related to the specifcity of the immunoconjugate, since the analogous treatment with an irrelevant immunotoxin showed therapeutic failure.

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Section: Discussionsupporting

confidence: 94%

“…Nevertheless, as previously suggested [ 18,29,33], the saccharide-binding ability of the ricin B chain should be not totally abolished by the steric hindrance of the antibody molecule on the linked ricin moiety.…”

Section: Discussionmentioning

confidence: 79%

Antitumour activity of a sterically blocked ricin immunotoxin on a human colorectal adenocarcinoma grafted subcutaneously in nude mice

Brusa¹,

Dosio²,

Pietribiasi³

et al. 1992

Cancer Immunol Immunother

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“…In most of these cases the drug antibody conjugates were specifically toxic, but most drugs suffered loss of potency during the conjugation procedure and were less toxic than a similar dose of free drug (18; 19). While there are many reasons for this, the most hkely is that insufficient amounts of drug are presented to the cells -due to the limitations on the amounts of drug which can be coupled to antibody with retention of both drug and antibody activity (17). There are several ways to overcome these problems: (i) use of more toxic analogues of the drugs to counteract the loss in drug activity; (ii) use of highly toxic proteins, such as ricin, where one molecule entering a cell is lethal and (iii) as examined herein, binding large amounts of drug to an inert carrier and then binding this drug-carrier complex to the antibody by only one site.…”

Section: Discussionmentioning

confidence: 99%

“…Over the last decade a number of antineoplastic drugs have been coupled to monoclonal antibodies to increase their specific reaction with tumour tissues (17). In most of these cases the drug antibody conjugates were specifically toxic, but most drugs suffered loss of potency during the conjugation procedure and were less toxic than a similar dose of free drug (18; 19).…”

Section: Discussionmentioning

confidence: 99%

Specific in vitro anti‐tumour activity of methotrexate‐monoclonal antibody conjugates prepared using human serum albumin as an intermediary

Pietersz

Cunningham

1988

Immunol Cell Biol

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Summary. Methotrexate (MTX) is a folic acid antagonist widely used in the treatment of cancer but, like other such agents, has non-specific toxic side effects. With the aim of reducing these toxic effects, MTX was coupled to monoclonal antibodies (MoAb) in one of two ways; either (a) directly using an active ester derivative or (b) via human serum albumin (HSA), to act as an intermediary and so increase the amount of MTX bound. The MTX coupled directly to anti-Ly-2.1 antibody had approximately 10 molecules of MTX per antibody molecule, whereas the HSA coupled material had 24 molecules of MTX per antibody molecule. After coupling MTX directly to antibody there was a loss of potency of the MTX, and MTXMoAb conjugates were 30-foId less potent than free MTX, although the antibody-coupled material was more specific than free MTX and bound only to the antibody-reactive target cells. By contrast, the MTX-HSA-MoAb conjugates were 3-5 times less potent than free MTX and were 8-5 times more potent than MTX-MoAb conjugates. Thus, by increasing the amount of drug bound to antibody, more toxic conjugates were made -an important principle for the use of such conjugates for the treatment of cancer in man.

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“…In order to achieve greater tumor specificity, numerous laboratories have explored the ability of tumor antibodies to serve as carriers for various radionuclides (Bejent, 1985;Pietersz et al, 1987;Eger et al, 1987;Woo et al, 1988). Studies in our own laboratory, on the other hand, have focused on drug molecules which have shown an ability to accumulate in tumors to serve as carriers of the radiodiagnostic probe (Counsel1 et al, 1969;Beierwaltes et al, 1968;Huang et al, 1979;Korn et al, 1979).…”

Section: Introductionmentioning

confidence: 99%

Selective localization of radioiodinated alkylphosphocholine derivatives in tumors

Plotzke

Haradahira

Stancato

et al. 1992

International Journal of Radiation Applications and Instrumenta

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We have designed and synthesized two radioiodinated analogs of hexadecylphosphocholine in order to evaluate their tumor imaging potential. 12-(m[125I]iodophenyl)dodecyl phosphocholine (NM-324) and hexadecyl-2-[N,N-dimethyl-N-(m[125I]iodobenzyl)-ammonium] ethyl phosphate (NM-326) demonstrated the ability of such compounds to localize in and thereby visualize the Walker 256 tumor in rats. However, the tumor avidity of NM-324 was far superior to NM-326. In addition, NM-324 showed excellent tumor localization in athymic mice bearing subcutaneous human tumors.

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The use of monoclonal antibody conjugates for the diagnosis and treatment of cancer

Cited by 29 publications

References 48 publications

Antitumour activity of a sterically blocked ricin immunotoxin on a human colorectal adenocarcinoma grafted subcutaneously in nude mice

Antitumour activity of a sterically blocked ricin immunotoxin on a human colorectal adenocarcinoma grafted subcutaneously in nude mice

Specific in vitro anti‐tumour activity of methotrexate‐monoclonal antibody conjugates prepared using human serum albumin as an intermediary

Selective localization of radioiodinated alkylphosphocholine derivatives in tumors

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