Anti-(transforming growth factor beta) antibodies with predefined specificity inhibit metastasis of highly tumorigenic human xenotransplants in nu/nu mice

Abstract

Monoclonal antibodies (mAb) were prepared against conjugated transforming growth factor beta 1 (TGF beta 1) peptides: amino acid positions 48-60 and positions 86-101. Two antibodies, mAb 16-3G1 [anti-(48-60)] and mAb 5-2G6 [anti-(86-101)] cross-reacted with native TGF beta 1, -beta 2 and -beta 3 (16-3G1) or only with native TGF beta 1 (5-2G6). Both mAb were used to characterize TGF beta-mediated effects on the metastatic potential in nude mice of human carcinoma cell line SLU-1 and its metastatic subline SLU-M1. Autocrine TGF beta 1-mediated up-regulation of cell proliferation and its suppression by anti-TGF beta antibodies in vitro was recorded for SLU-M1 cells whereas SLU-1 cell proliferation in vitro appeared to be refractory to anti-TGF beta antibodies and exogenous TGF-beta 1. However, the potential of s.c. tumours to develop distant metastases in nude mice was about the same for both cell lines. Development of primary tumours and distant metastases could be suppressed by treatment of mice with anti-TGF beta antibodies. Thus we assume that the metastatic potential of tumour cells is independent of TGF beta-mediated growth-regulation effects in vitro. The anti-TGF beta-induced suppression of tumour progression and metastasis in nude mice might rather result from stimulation of the immune surveillance. TGF beta-mediated autocrine down-regulation of MHC-unrestricted cytotoxicity of activated human monocytes and CD56+ LAK cells and its reversion by anti-TGF beta antibodies could be readily demonstrated. In all our experimental series, the neutralizing potential of both anti-TGF beta antibodies, though directed against opposite sites of the TGF beta 1 molecule, was very similar.