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Inhibition of human renal cancer by monoclonal-anti-body-linked methotrexate in an ascites tumor model
1Department of Pharmacy, Dalhousie University, Halifax, Nova Scotia, Canada.
Abstract:
The monoclonal antibody DAL K29 against a cell-surface antigen associated with a human renal cell carcinoma was covalently linked to the antifolate methotrexate with full retention of antibody activity and partial retention of drug activity. Using an ascites tumor model, developed after intraperitoneal (i.p.) inoculation of 5 x 10(6) cells of the human kidney cancer line Caki-1 per pristane-primed nude mouse, we showed that the methotrexate-Dal-K29 conjugate was a more potent tumor inhibitor (P less than 0.0005) of human renal cell carcinoma (which is resistant to currently available modalities including chemotherapy) than the drug or mAb alone, the drug linked to an isotype-matched nontumor-specific IgG or a mixture of the drug and the mAb. Only the conjugate could produce tumor-free survival in a proportion of the mice during the period of observation (i.e. 150 days after tumor inoculation).
Insights
A novel antibody-drug conjugate targeting renal cell carcinoma demonstrated superior tumor inhibition and achieved tumor-free survival in mice. This methotrexate-Dal-K29 conjugate offers a promising new strategy for treating resistant kidney cancer.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- Human renal cell carcinoma (RCC) often presents resistance to conventional chemotherapy.
- Targeted therapies are crucial for improving treatment outcomes in refractory cancers.
- Monoclonal antibodies (mAbs) can be utilized for targeted drug delivery.
Purpose of the Study:
- To develop and evaluate a novel antibody-drug conjugate (ADC) for treating human renal cell carcinoma.
- To assess the efficacy of a methotrexate-Dal-K29 conjugate in a preclinical cancer model.
- To compare the antitumor activity of the ADC against its individual components and control treatments.
Main Methods:
- Covalent linkage of the antifolate methotrexate to the monoclonal antibody DAL K29, targeting a cell-surface antigen on RCC.
- Establishment of an ascites tumor model using human kidney cancer line Caki-1 in nude mice.
- Administration of the methotrexate-Dal-K29 conjugate, free drug, free mAb, drug-IgG conjugate, or drug-mAb mixture.
- Evaluation of tumor inhibition and survival rates over a 150-day observation period.
Main Results:
- The methotrexate-Dal-K29 conjugate exhibited significantly enhanced tumor inhibition compared to the free drug, mAb, or control conjugates (P < 0.0005).
- Full retention of antibody activity and partial retention of drug activity were observed in the conjugate.
- Only the methotrexate-Dal-K29 conjugate achieved tumor-free survival in a proportion of the treated mice.
Conclusions:
- The developed methotrexate-Dal-K29 antibody-drug conjugate is a potent inhibitor of human renal cell carcinoma.
- This ADC represents a promising therapeutic strategy for chemoresistant RCC.
- Targeted delivery of antifolates via specific monoclonal antibodies can overcome drug resistance in cancer treatment.