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Increased antitumor effect of immunoconjugates and tumor necrosis factor in vivo
M J Smyth1, G A Pietersz, I F McKenzie
1Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
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.
Insights
This study shows that combining N-Acetyl-melphalan-monoclonal antibody (N-AcMEL-MoAb) conjugates with recombinant human tumor necrosis factor alpha (rTNF-alpha) can effectively eradicate larger tumors. This combination therapy enhances the antitumor activity of drug-antibody conjugates in vivo.
Area of Science:
- Oncology
- Immunotherapy
- Drug Delivery
Background:
- Monoclonal antibody (MoAb) drug conjugates target antineoplastic drugs to tumors.
- N-Acetyl-melphalan-MoAb (N-AcMEL-MoAb) conjugates show antitumor activity but struggle to eradicate larger tumors due to limited tumor penetration.
- Recombinant human tumor necrosis factor alpha (rTNF-alpha) induces tumor necrosis.
Purpose of the Study:
- To investigate the potential of combining N-AcMEL-MoAb conjugates with rTNF-alpha to enhance antitumor efficacy.
- To determine if rTNF-alpha can potentiate the ability of N-AcMEL-MoAb conjugates to eradicate larger established tumors.
Main Methods:
- Murine thymoma models in mice were treated with N-AcMEL-MoAb conjugates alone, rTNF-alpha alone, or a combination of both.
- Tumor size and regression were monitored to assess treatment efficacy.
Main Results:
- Combination therapy with N-AcMEL-MoAb conjugates and rTNF-alpha resulted in partial or complete regression of 30% of larger tumors (0.4-0.6 cm2).
- No tumor regressions were observed in groups treated with N-AcMEL-anti-Ly-2.1 conjugate or rTNF-alpha alone.
- rTNF-alpha enhanced the in vivo antitumor effect and tumor localization of N-AcMEL-MoAb conjugates.
Conclusions:
- Combination therapy with rTNF-alpha significantly enhances the efficacy of N-AcMEL-MoAb conjugates.
- This approach enables the eradication of larger, established tumors that are resistant to drug-antibody conjugates alone.
- The findings suggest a promising strategy for improving cancer treatment outcomes with targeted therapies.