Antibody-drug conjugates in oncology: A spotlight on overcoming resistance

Area of Science:

• Oncology
• Pharmacology
• Biotechnology

Background:

• Antibody-drug conjugates (ADCs) are advanced cancer therapeutics combining targeted antibodies with potent cytotoxic drugs.
• Despite significant clinical success, the development of resistance mechanisms limits the long-term efficacy of ADCs.
• Understanding these resistance pathways is crucial for improving patient outcomes in cancer treatment.

Purpose of the Study:

• To systematically review the diverse mechanisms contributing to antibody-drug conjugate resistance.
• To evaluate emerging strategies and novel therapeutic approaches designed to overcome ADC resistance.
• To provide a comprehensive framework for enhancing ADC efficacy in oncological applications.

Main Methods:

• Systematic literature review of preclinical and clinical studies on ADC resistance.
• Analysis of factors contributing to resistance, including antibody, trafficking, payload, and signaling pathways.
• Evaluation of therapeutic strategies such as next-generation ADCs, novel payloads, and combination therapies.

Main Results:

• ADC resistance involves complex mechanisms related to antibody binding, intracellular trafficking, payload activity, and cancer cell survival signaling.
• Third-generation ADCs, innovative payloads, and combination therapies show potential in preclinical models.
• These strategies aim to circumvent or overcome identified resistance pathways.

Conclusions:

• Overcoming ADC resistance is critical for maximizing their therapeutic potential in oncology.
• A deeper understanding of resistance mechanisms informs the development of more effective ADC-based treatments.
• Integrating preclinical findings with clinical data is essential for advancing ADC therapy and improving cancer patient care.