Increased antitumor effect of immunoconjugates and tumor necrosis factor in vivo

Cancer Res. 1988 Jul 1;48(13):3607-12.

Abstract

The potential of specifically targeting antineoplastic drugs and toxins to tumors with the use of monoclonal antibodies (MoAbs) reactive with tumor-associated antigens is currently being examined. N-Acetyl-melphalan-MoAb (N-AcMEL-MoAb) conjugates have previously been shown to have greater antitumor activity than N-AcMEL, melphalan, or MoAb alone against both subcutaneous and ascites murine thymomas in mice (1). Although this conjugate is also a highly selective tumor inhibitor in vitro, it may not reach all the tumor cells in a high concentration, and consequently larger tumors (greater than 0.4 cm2) cannot be eradicated. This conjugate is representative of many drug-MoAb conjugates in that they are unable to gain adequate access to the tumor site to exert their cytotoxic effect. To potentiate the antitumor effect of the N-AcMEL-MoAb conjugate, studies were undertaken to analyze its action in combination with recombinant human tumor necrosis factor alpha (rTNF-alpha), a monokine, capable of causing acute necrosis of syngeneic tumor transplants in mice. Treatment of mice with murine thymomas (0.4 to 0.6 cm2 in size) demonstrated that 30% of the tumors in mice receiving conjugate and rTNF-alpha partially or completely regressed, while no regressions were observed in the tumors of mice receiving N-AcMEL-anti-Ly-2.1 conjugate or rTNF-alpha alone. This and other experiments indicated that the antitumor effect and tumor localization of N-AcMEL-MoAb conjugates can be enhanced in vivo by rTNF-alpha, thereby enabling successful eradication of larger established subcutaneous murine tumors.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents*
  • Immunotherapy
  • Immunotoxins / metabolism
  • Immunotoxins / therapeutic use*
  • Mice
  • Recombinant Proteins / therapeutic use
  • Thymoma / therapy*
  • Tissue Distribution
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / therapeutic use*

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Immunotoxins
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha