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.