Dipeptide-based highly potent doxorubicin antibody conjugates

Area of Science:

• Medicinal Chemistry
• Oncology
• Immunology

Background:

• Doxorubicin is a potent chemotherapy agent with limitations in targeted delivery.
• Monoclonal antibodies (mAbs) offer specific targeting of cancer cells.
• Developing effective antibody-drug conjugates (ADCs) requires precise control over drug release.

Purpose of the Study:

• To synthesize and evaluate novel doxorubicin derivatives conjugated to monoclonal antibodies for targeted cancer therapy.
• To investigate drug linker strategies for controlled release of potent doxorubicin derivatives upon cellular uptake.
• To assess the efficacy and selectivity of these antibody-drug conjugates against specific cancer types.

Main Methods:

• Synthesis of novel doxorubicin derivatives and their conjugation to monoclonal antibodies (mAbs) using specific linker strategies.
• Evaluation of drug linker hydrolysis by lysosomal enzymes, specifically cathepsin B.
• Assessment of the cytotoxic activity of antibody-drug conjugates against antigen-positive and antigen-negative cancer cell lines.

Main Results:

• Two novel drug linker strategies were successfully employed to attach potent doxorubicin derivatives to mAbs.
• The drug linkers were shown to be substrates for cathepsin B, enabling controlled drug release.
• The resulting antibody-drug conjugates demonstrated potent and immunologically selective activity against renal cell carcinoma and anaplastic large cell lymphoma cell lines.

Conclusions:

• Novel doxorubicin derivatives can be effectively conjugated to monoclonal antibodies for targeted drug delivery.
• The developed linker strategies allow for controlled drug stability and release, enhancing therapeutic potential.
• These antibody-drug conjugates represent a promising approach for selective cancer treatment.