Combination cancer therapy by hapten-targeted prodrug-activating enzymes and cytokines

Area of Science:

• Oncology
• Biotechnology
• Immunotherapy

Background:

• Heterogeneous tumors present challenges for single-agent therapies.
• Targeted delivery systems are crucial for enhancing combination therapy efficacy.
• Engineering cancer cells to express specific receptors can enable targeted drug delivery.

Purpose of the Study:

• To investigate the targeted delivery of multiple therapeutic agents to cancer cells expressing anti-dansyl single-chain antibodies (DNS scFv).
• To evaluate the efficacy of combination therapy using DNS-modified agents in a preclinical cancer model.
• To assess the potential of this approach for treating heterogeneous tumors.

Main Methods:

• CT-26 colon cancer cells were engineered to express DNS scFv.
• Recombinant proteins (beta-glucuronidase and IL-2) were conjugated with dansyl moieties and linkers.
• The conjugates were evaluated for binding specificity, enzymatic activity, and in vivo tumor accumulation.
• Therapeutic efficacy was assessed through combination treatment regimens.

Main Results:

• DNS scFv were stably expressed on cancer cells both in vitro and in vivo.
• DNS-modified conjugates selectively bound to DNS scFv-expressing cells.
• Targeted delivery of DNS-PEG-betaG activated a prodrug, and both DNS-PEG-betaG and DNS-PEG-IL-2 delayed tumor growth.
• Combination therapy significantly suppressed tumor growth compared to single-agent treatments.

Conclusions:

• Selective delivery of multiple DNS-modified therapeutic agents to DNS scFv receptors is feasible in vitro and in vivo.
• This targeted combination therapy approach shows significant potential for treating DNS scFv-modified tumors.
• The strategy offers a novel platform for overcoming limitations in heterogeneous tumor treatment.