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Tissue localization of methotrexate-monoclonal-IgM immunoconjugates: Anti-SSEA-1 and MOPC 104E in mouse teratocarcinomas and normal tissues

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Summary

Methotrexate (MTX) was coupled to the tumor-targeting monoclonal IgM, anti-SSEA-1 and the nontargeting 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.

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Author notes

  1. Stefano Persiani

    Present address: Department of Pharmakokinetics and Metabolism, Farmitalia Carlo Erba, Via Imbonati 24, 20159, Milano, Italy

Authors and Affiliations

  1. Division of Urological Surgery, University of Pittsburgh, 15261, Pittsburgh, PA, USA

    Byron Ballou, Stefano Persiani & Thomas R. Hakala

  2. VAMC, University Drive C, 15240, Pittsburgh, PA, USA

    Byron Ballou, Jean M. Reilandu & Thomas R. Hakala

  3. Pittsburgh Cancer Institute, 15213, Pittsburgh, PA, USA

    Byron Ballou, Stefano Persiani & Thomas R. Hakala

  4. Department of Pathology, Children's Hospital, 15213, Pittsburgh, PA, USA

    Ronald Jaffe & Joseph Curley

  5. School of Pharmacy, University of Southern California, 90033, Los Angeles, CA, USA

    Stefano Persiani & Wei-Chiang Shen

  6. Department of Medicine, Baylor College of Medicine, 77030, Houston, TX, USA

    John J. Langone

  7. Dupont Merck, Experimental Station, 19880-0328, Wilmington, DE, USA

    Howard Sands

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  1. Byron Ballou
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  4. Wei-Chiang Shen
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  7. Jean M. Reilandu
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  9. Thomas R. Hakala
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Supported by intramural research funds of the VAMC and by the Division of Urological Surgery, University of Pittsburgh

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Ballou, B., Jaffe, R., Persiani, S. et al. Tissue localization of methotrexate-monoclonal-IgM immunoconjugates: Anti-SSEA-1 and MOPC 104E in mouse teratocarcinomas and normal tissues. Cancer Immunol Immunother 35, 251–256 (1992). https://doi.org/10.1007/BF01789331

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  • DOI: https://doi.org/10.1007/BF01789331

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