Mechanisms of Resistance to Monoclonal Antibodies (mAbs) in Lymphoid Malignancies

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Therapeutic monoclonal antibodies (mAbs) have transformed cancer treatment, particularly hematological malignancies.
• Despite improved outcomes, resistance to mAbs is a significant challenge, impacting long-term patient survival.
• This review examines resistance mechanisms to rituximab and other mAbs used in hematological cancers.

Purpose of the Study:

• To review current data on mechanisms of resistance to therapeutic monoclonal antibodies (mAbs) in hematological malignancies.
• To explore strategies for overcoming mAb resistance.
• To identify clinically relevant resistance factors.

Main Methods:

• Literature review of existing data on mAb resistance mechanisms.
• Analysis of identified resistance pathways including antigen expression, cytotoxicity, signaling, and cell death.
• Exploration of novel therapeutic approaches targeting the tumor microenvironment and apoptosis.

Main Results:

• Resistance mechanisms affect all aspects of mAb function, including antigen binding, complement-mediated cytotoxicity (CMC), antibody-dependent cellular cytotoxicity (ADCC), and direct cell death induction.
• While numerous strategies are under investigation, clinically relevant mechanisms remain incompletely understood.
• Emerging research highlights the tumor microenvironment and apoptotic pathways as critical areas for overcoming resistance.

Conclusions:

• Resistance to mAbs in hematological malignancies is multifactorial, influenced by patient, disease, and antibody-specific factors.
• A comprehensive understanding of resistance mechanisms is essential for developing effective therapeutic strategies.
• Future research should focus on overcoming resistance to improve long-term outcomes for cancer patients treated with mAbs.