Tissue localization of methotrexate-monoclonal-IgM immunoconjugates: anti-SSEA-1 and MOPC 104E in mouse teratocarcinomas and normal tissues.
Methotrexate (MTX) was coupled to the tumor-targeting monoclonal IgM, anti-SSEA-1 and the non-targeting myeloma IgM, MOPC 104E. At 24-h intervals following injection, drug deposition in MH-15 teratocarcinomas and in several normal tissues was followed by immunoperoxidase microscopy using the M16 monoclonal antibody to MTX. MTX-anti-SSEA-1 was deposited on the surface and in the interior of living tumor cells 24 h after injection; at 48 h and after, only low-level binding to necrotic tissue was found. There was no significant gradation in staining from the outside to the interior of the tumors. In tumors, the control MOPC 104E immunoconjugate was detectable only in necrotic tissue. Binding to SSEA-1-expressing normal tissues was undetectable, except for pericryptal fibroblasts in the small intestine. No significant pathology was found in normal tissues that are SSEA-1 positive. High levels of the immunoconjugate were detected in the liver, where MTX was found predominantly in Kupffer cells and possibly in hepatocytes; again, no significant morphological changes were associated with this retention. Thus tumor-associated antigens can be suitable targets for antibody-drug conjugates even when present in normal tissues and in large quantities, provided that the antigens in normal tissues are inaccessible. Moreover, deposition in viable tumor tissue can be assessed using monoclonal antibodies to methotrexate.
Division of Urological Surgery, University of Pittsburgh, PA 15261.
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Ballou
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Jaffe
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Persiani
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Shen
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Langone
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Sands
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Reilandu
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Curley
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Hakala
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D000922:Immunotoxins / Q000378:metabolism*; D016256:Lewis X Antigen / Q000276:immunology; D008727:Methotrexate / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009194:Myeloma Proteins / Q000276:immunology; D009368:Neoplasm Transplantation; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M; D000922:Immunotoxins; D016256:Lewis X Antigen; D009194:Myeloma Proteins; D008727:Methotrexate