Effect of tumor necrosis factor on the antitumor efficacy and toxicity of aminopterin-monoclonal antibody conjugates: parameters for optimization of therapy.

Immunoconjugates of monoclonal antibodies with drugs, isotopes, or toxins are currently being investigated for their therapeutic effect on tumors. However, all have problems of access of the immunoconjugate to the tumor, particularly with solid tumors. To address this problem, we have used aminopterin-monoclonal antibody (AMN-mAb) conjugates combines with murine tumor necrosis factor (mTNF-alpha), which is known to have specific effects on tumor vasculature. In a murine model, well-established tumors (measuring 1.0-1.4 cm in diameter) were either totally eradicated or considerably reduced in size with combined therapy--a greater effect than with either mTNF-alpha or AMN-mAb used alone. The mechanisms involved in the improved antitumor effect were investigated using in vitro assays, autoradiography, and biodistribution experiments. mTNF-alpha was found both to increase the cytotoxic activity of the conjugate in vitro and to increase in vivo tumor localization of mAb up to 5-fold. The timing of mTNF-alpha administration was crucial to effects on tumor localization; mTNF-alpha given with mAb caused the greatest increase in localization and mTNF-alpha given well before mAb decreased localization. mTNF-alpha also reduced the toxicity to mice of AMN-mAb depending on the timing of injection. These results indicate that mTNF-alpha has a useful role in potentiation of immunoconjugate therapy but shows the need for careful planning of the dose regimen.