Editor’s Note: Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has rapidly advanced in the treatment of lung cancer in recent years. However, challenges remain, such as limited efficacy with monotherapy and increased side effects with combination therapies. Multi-targeted combination therapies represent a potential avenue for advancing immunotherapy. Among them, bispecific antibodies (BsAbs), which simultaneously target two different antigens or epitopes, have emerged as a focus of attention for their ability to enhance the immune system's recognition and destruction of tumor cells.

At the 2024 Chinese Congress on Holistic Integrative Oncology (CCHIO) held on November 17, Dr. Huaqing Wang from Nankai University Tianjin People’s Hospital delivered a keynote speech titled “Exploring Bispecific Antibodies in Lung Cancer,” focusing on the latest research progress in this field and prospects for future exploration. Below is a summary of the key points shared.

Part 1: Overview of Bispecific Antibody Development

1. Introduction to Bispecific Antibodies

Bispecific antibodies (BsAbs) are engineered using cell fusion, recombinant DNA, and protein engineering techniques. Unlike monoclonal antibodies (mAbs), BsAbs can bind two antigens or different epitopes of the same antigen simultaneously or sequentially, making them a unique therapeutic agent.

• Since their concept in 1960, BsAbs have evolved significantly. As of October 2024: 12 BsAbs have been approved by the NMPA/FDA for cancer treatment (7 for hematological malignancies and 5 for solid tumors). Over 470 BsAbs are in clinical trials globally, with 1,000+ in preclinical development.

2. Structural Classification of BsAbs

1. Fc-Containing (IgG-like):
2. These BsAbs resemble IgG antibodies and retain Fc-mediated functions (e.g., ADCC, CDC, or ADCP). Examples include Amivantamab-vmjw and Envafolimab.
3. Non-Fc-Containing (Non-IgG-like):
4. These BsAbs are designed without Fc fragments, avoiding chain cross-linking issues. They primarily rely on antigen-binding properties, with faster clearance rates and shorter half-lives. Examples include Blinatumomab.

3. Mechanisms of Action

• T-cell Redirection: Targets CD3 to link tumor and immune cells, promoting immune-mediated tumor killing (e.g., BsAbs for hematological cancers).
• Dual Signal Inhibition: Blocks aberrantly expressed receptors on tumor cells, inhibiting growth signals (e.g., EGFR×MET BsAbs).
• Biparatopic Targeting: Binds two distinct epitopes on the same antigen to block critical pathways (e.g., HER2×HER2 BsAbs).
• Checkpoint Blockade: Modulates two immune checkpoint pathways (e.g., PD-1×CTLA-4 BsAbs).

4. Development Trends in China vs. Globally

• Globally: Research focuses on T-cell redirection, especially CD3-based targets.
• China: Emphasis is on dual immune checkpoint blockade, particularly PD-1/PD-L1 pathways.

Part 2: Progress in Bispecific Antibodies for Lung Cancer

1. PD-L1×TGF-β Bispecific Antibodies

• Bintrafusp Alfa (M7824):
• Early trials showed some efficacy but failed to meet endpoints in Phase III studies, leading to discontinuation in NSCLC.
• SHR-1701:
• Demonstrated promising efficacy in EGFR-TKI-resistant and immune-refractory NSCLC patients in Phase I studies, with Phase III trials ongoing.

2. PD-(L)1×CTLA-4 Bispecific Antibodies

• Cadonilimab (AK104):
• Approved for cervical cancer, it has shown efficacy in NSCLC, with encouraging ORR and tolerability.
• Volrustomig (MEDI5752):
• Improved survival outcomes in NSCLC patients with low PD-L1 expression and is now in Phase III trials.

3. PD-1×VEGF Bispecific Antibodies

• Envafolimab (AK112):
• Approved for EGFR-TKI-resistant NSCLC, showing significant improvement in PFS and OS compared to standard care.

4. DLL3×CD3 Bispecific Antibodies

• Tarlatamab (AMG757):
• Achieved FDA approval for recurrent small cell lung cancer (SCLC) with remarkable efficacy.
• BI 764532:
• Demonstrated encouraging signals in refractory SCLC, with manageable safety profiles.

Part 3: Challenges and Future Directions

1. Clinical Challenges

BsAbs are designed to address clinical gaps, such as improving safety, increasing efficacy, and overcoming resistance.

2. Advantages of BsAbs

• Enhanced immune activation and tumor specificity.
• Reduced off-target effects and toxicity.
• Improved tumor internalization and immune response modulation.

3. Future Directions

• Expanding applications in resistant lung cancer subtypes.
• Targeting tumor microenvironments.
• Addressing resistance mechanisms through innovative BsAb combinations.

Conclusion

Professor Wang emphasized that bispecific antibodies represent a transformative approach in lung cancer immunotherapy, offering solutions to overcome existing treatment limitations. With ongoing clinical developments, BsAbs are set to redefine therapeutic strategies and improve patient outcomes significantly.

Dr. Huaqing Wang

• MD, Chief Physician, Professor, PhD Supervisor
• Director of the Oncology Diagnosis and Treatment Center, Nankai University Tianjin People’s Hospital
• Director of the National Drug Clinical Trial Institution
• Director of the Tianjin Institute of Tumor Research Combining Traditional Chinese and Western Medicine
• Former Chair of the Fourth Lymphoma Committee, Chinese Anti-Cancer Association
• Executive Committee Member, Chinese Society of Clinical Oncology (CSCO)
• Vice Chair, Tumor Chemotherapy Committee, Chinese Anti-Cancer Association
• Standing Member, Tumor Targeted Therapy Committee, Chinese Anti-Cancer Association