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Development of a Severe Combined Immunodeficiency (SCID) Mouse Model Consisting of Highly Disseminated Human B-Cell Leukemia/Lymphoma, Cure of the Tumors by Systemic Administration of Immunotoxin, and Development/Application of a Clonotype-specific Polymerase Chain Reaction-based Assay¹

Departments of Molecular Immunology [M. Y., R. J. R., A. K., F. M., H. T., B. K. S.], Neurology [Y. C., S. J. G.], and Pathology [M. B.], Roswell Park Cancer Institute, ^,3 Buffalo, New York 14263

A new severe combined immunodeficiency (SCID) mouse model consisting of highly disseminated human B-cell leukemia/lymphoma was developed by i.v. inoculation of BALL-1a, an in vivo adapted malignant B-cell line. A 100% transplantability was achieved in nonpreconditioned SCID mice using various BALL-1a doses between 2.5 x 10⁴ and 6 x 10⁶ cells. Hind-leg paralysis preceded the death of the mice.

Utility of the developed tumor model for the therapeutic studies was investigated by i.v. administration of an anti-B-cell monoclonal antibody SN7 (IgG1) and its conjugate with deglycosylated ricin A chain (dgRA). The therapy was initiated 2, 4, or 6 days after tumor inoculation using 4 x 24 µg of SN7-dgRA or 4 x 20 µg of SN7; the total dose (96 µg) of SN7-dgRA corresponded to 14% of the LD₅₀ dose. SN7-dgRA showed a strong antitumor efficacy in all groups of treated mice. All of the day-2 group mice (n = 7) and six (66.7%) of the day-4 group mice (n = 9) survived healthily for as long as followed (240 days), whereas four (57.1%) of the day-6 group mice (n = 7) survived healthily for as long as followed (200 days). Unconjugated SN7 showed a significant antitumor efficacy but was less effective than SN7-dgRA.

A PCR-based assay specific for the clonogenic BALL-1a tumor was developed and applied to determine tumors in various organs of BALL-1a-bearing SCID mice. The assay was highly sensitive in screening for trace quantities of residual tumors in various organs of SCID mice, and it could detect 1 malignant cell/2.5 x 10⁵ tissue cells. The PCR-based assay was shown to be much more powerful than the conventional histological analysis in detecting residual tumors. Furthermore, we could estimate quantities of the detected tumors by the PCR-based assay. It is remarkable to find that all examined organs of some of the SN7-dgRA-treated mice were tumor-free as determined by the clonotype-specific PCR-based assay.

The present results show the usefulness of the newly developed SCID mouse model, SN7-dgRA, and the clonotype-specific PCR-based molecular assay for the study of therapy of human B-cell leukemia/lymphoma.

¹ Supported by American Cancer Society Grant IM-741 and in part by USPHS Grant CA16056.

² To whom requests for reprints should be addressed.

³ A unit of the New York State Department of Health. Roswell Park Cancer Institute is a National Cancer Institute-designated comprehensive cancer center.

Received 1/10/96. Accepted 12/18/96.

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