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Targeting of human glioma xenografts in vivo utilizing radiolabeled antibodies
J A Williams1, B W Wessels, M D Wharam
1Division of Radiation Oncology, Johns Hopkins Oncology Center, Baltimore, MD 21205.
Abstract:
Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal and polyclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein, and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (microCi) of tumor activity per gram per 100 microCi injected activity compared to 4.5 microCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The proportion of tumor dose found in normal organs is less than 10%, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, and polyclonal rabbit antiferritin, which defines a tumor-associated antigen, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. When compared to the 111In-radiolabeled antibody, 90Y-radiolabeled P96.5 demonstrates comparable tumor targeting and percentages of tumor dose found in normal organs. To test the therapeutic potential of 90Y-radiolabeled P96.5, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Seven days following administration of 100 microCi 90Y-radiolabeled P96.5, average absorbed doses of 3770, 980, 353, and 274 cGy were observed in tumor, liver, contralateral control site, and total body, respectively. Shared cell surface antigens among neuroectodermally derived neoplasms provide a basis for exploration of human glioma radioimmunotherapy.
Insights
Radiolabeled monoclonal antibody P96.5 shows specific targeting of human glioma xenografts in mice. This targeted delivery of radiation offers a promising approach for human glioma radioimmunotherapy.
Area of Science:
- Oncology
- Immunology
- Radiochemistry
Background:
- Radiolabeled antibodies are being explored for targeted radiotherapy of human gliomas.
- Effective targeting requires antibodies that specifically bind to glioma-associated antigens.
Purpose of the Study:
- To evaluate the tumor targeting capabilities of radiolabeled monoclonal and polyclonal antibodies against human glioma xenografts in nude mice.
- To assess the therapeutic potential of these radiolabeled antibodies for glioma radioimmunotherapy.
Main Methods:
- Human glioma xenografts in nude mice were used to test antibody targeting.
- Immunoperoxidase histochemistry was employed to measure antibody binding.
- Tumor and normal organ activity were quantified after administration of radiolabeled antibodies (¹¹¹In and ⁹⁰Y).
- Therapeutic potential was assessed by measuring absorbed doses in tumors and normal tissues using thermoluminescent dosimeters (TLDs).
Main Results:
- Monoclonal antibody P96.5 specifically targeted U-251 human glioma xenografts, showing significantly higher tumor activity compared to irrelevant antibodies.
- Targeting ratios indicated an 11.6-fold greater deposited dose with radiolabeled P96.5.
- Less than 10% of the tumor dose was found in normal organs, confirming specific targeting.
- ⁹⁰Y-radiolabeled P96.5 demonstrated comparable tumor targeting and biodistribution to ¹¹¹In-labeled P96.5.
- Significant absorbed doses were delivered to tumors (3770 cGy) with acceptable levels in normal tissues after ⁹⁰Y-P96.5 administration.
Conclusions:
- Monoclonal antibody P96.5 exhibits specific targeting of human gliomas, supporting its potential use in radioimmunotherapy.
- Shared cell surface antigens in neuroectodermal tumors provide a rationale for developing glioma radioimmunotherapy strategies.
- ⁹⁰Y-labeled P96.5 shows promise as a therapeutic agent for human gliomas.
