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Involvement of B Lymphocytes in the Growth Inhibition of Human Pulmonary Melanoma Metastases in Athymic nu/nu Mice by an Antibody-Lymphotoxin Fusion Protein¹

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037 [R. A. R., J. C. B.]; Fuji ImmunoPharmaceuticals Corporation, Lexington, Massachusetts 02173 [S. D. G.]; Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [J. M.]; and Department of Pathology, School of Medicine, University of California, La Jolla, California 92037 [N. M. V.]

Antibody-cytokine fusion proteins can target biologically active cytokines to various tumor sites, achieving local concentrations sufficient to induce host immune responses leading to tumor elimination. Here, we demonstrate the therapeutic efficacy of a tumor-specific antibody-lymphotoxin fusion protein (ch225-LT) on xenografted pulmonary metastases of human melanoma. In vitro studies indicated a direct cytotoxic effect of such constructs on melanoma cells via the induction of apoptosis, as demonstrated by cell cycle analysis and DNA fragmentation. However, ch225-LT lacked any therapeutic effect in immune deficient C.B17 scid/beige and scid/scid mice, indicating the insufficiency of this direct mechanism in vivo. In contrast, in athymic nu/nu mice, ch225-LT completely inhibited outgrowth of the xenografted tumor. This therapeutic effect was accompanied by infiltrations of CD45+, Mac-1+, and asialo-GM1+ cells into the tumor; B220+ cells were present in the surrounding tissue and the periphery of the tumor. The functional role of asialo-GM1+ cells was confirmed by in vivo depletion studies. Our data indicate that an antibody-lymphotoxin fusion protein effectively inhibits the growth of disseminated melanoma metastases by mechanisms that function in the absence of mature T cells, but require B, NK, and other asialo-GM1+ cells.

¹ This work was supported in part by Outstanding Investigator Grant CA42508-10 (to R. A. R.). J. C. B. is a fellow of the Deutsche Forschungs Gemeinschaft. This is The Scripps Research Institute Manuscript No. 9958-IMM.

² To whom requests for reprints should be addressed, at Department of Immunology, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037.

Received 1/22/96. Accepted 3/ 1/96.

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