For a comprehensive overview of approved PD-1/CTLA-4 bispecific antibodies and other immune checkpoint inhibitors in China, see:

Approved Immune Checkpoint Inhibitors in China: PD-1, PD-L1, CTLA-4 and Bispecific Antibodies

Biological Mechanisms of CTLA-4 and PD-1

CTLA-4 and PD-1 are both key negative regulatory molecules in T-cell immune checkpoint pathways, but they differ in their sites and stages of action:

CTLA-4 primarily functions during the early activation phase of T cells, mainly in lymph nodes, where it competes with CD28 for binding to CD80/CD86, thereby inhibiting T-cell activation and proliferation.

PD-1 primarily acts in peripheral tissues and the tumor microenvironment by binding to PD-L1/PD-L2 and suppressing T-cell effector function.

These mechanistic differences make CTLA-4 and PD-1 complementary in immune regulation and provide a theoretical basis for combination or dual-target inhibition strategies.

CTLA-4 Target and Clinical Applications

CTLA-4 belongs to the CD28 immunoglobulin superfamily and is an important inhibitory immune receptor. Several CTLA-4-targeting drugs have been approved globally:

● Ipilimumab (Yervoy), the first CTLA-4 monoclonal antibody, approved for melanoma, renal cell carcinoma, and other indications

● Tremelimumab (Imjudo), approved for hepatocellular carcinoma and non-small cell lung cancer

In China, domestic companies are also advancing CTLA-4-related development:

● IBI310 (an ipilimumab biosimilar/CTLA-4-targeting agent developed by Innovent Biologics) has submitted a marketing authorization application

● A combination therapy involving sintilimab and a CTLA-4 antibody has been accepted for review by the NMPA

PD-1 Pathway and Clinical Role

PD-1 is broadly expressed on activated T cells, B cells, and myeloid cells. It suppresses immune responses through interaction with PD-L1. The PD-1/PD-L1 axis plays a key role in tumor immune evasion.

Nivolumab is a fully human IgG4 monoclonal antibody targeting PD-1 that has been approved for use in multiple countries and regions worldwide. Its indications include various solid tumors such as non-small cell lung cancer, renal cell carcinoma, melanoma, and gastric cancer.

Pembrolizumab is also a globally approved PD-1 inhibitor with a similar mechanism of action. Its indications include non-small cell lung cancer, melanoma, Hodgkin lymphoma, and gastric cancer, with more pronounced clinical benefits observed in patients with high PD-L1 expression or MSI-H/dMMR status.

However, PD-1 monotherapy mainly acts on pre-existing T cells within the tumor microenvironment, resulting in limited efficacy in “immune-cold” tumors, and acquired resistance remains a clinical challenge.

Design Rationale of PD-1/CTLA-4 Bispecific Antibodies

PD-1/CTLA-4 bispecific antibodies (BsAbs) are engineered to simultaneously target two immune checkpoints within a single molecule, enabling dual blockade.

Key features include:

● Simultaneous inhibition of early T-cell activation and peripheral immune suppression

● Improved immune response efficiency within the tumor microenvironment

● Reduced systemic toxicity compared to combination therapies

● Optimized pharmacokinetics through antibody engineering

These agents aim to achieve a balance between efficacy and safety.

Global Development of PD-1/CTLA-4 Bispecific Antibodies

Multiple PD-1/CTLA-4 bispecific antibodies are currently in various stages of clinical development, including MGD019, MEDI5752 (Volrustomig), and KN046, with some advancing into pivotal clinical trials.

Approved Representative Drugs in China

Cadonilimab (AK104)

Cadonilimab, developed jointly by Akeso and collaborators, is the world’s first approved PD-1/CTLA-4 bispecific antibody.

● Approved indications: recurrent or metastatic cervical cancer, gastric cancer, etc.

● Mechanism: dual targeting of PD-1 and CTLA-4

● Structural feature: tetravalent bispecific antibody design reducing Fc receptor-mediated toxicity

● Clinical feature: demonstrated efficacy even in PD-L1 low-expressing populations

Iparomlimab (QL1706)

QL1706, developed by Qilu Pharmaceutical, is another PD-1/CTLA-4 bispecific antibody approved in China.

● Approval year: 2024

● Indication: recurrent or metastatic cervical cancer after platinum-based chemotherapy failure

● Feature: dual-target synergistic design enhancing T-cell anti-tumor activity

Other Investigational Agents

● Volrustomig (MEDI5752, AstraZeneca): designed for selective activity in PD-1-positive activated T cells

● KN046: demonstrated objective response rates and is being evaluated across multiple solid tumors

Clinical Significance and Development Trends

The development of PD-1/CTLA-4 bispecific antibodies represents an evolution from single-target blockade to multi-target immune modulation.

Compared with traditional combination therapies, this strategy may offer advantages in dosing convenience, tumor selectivity, and toxicity control.

Current research focuses include:

● Improving response rates across tumor types

● Optimizing patient stratification strategies

● Reducing immune-related adverse events

● Expanding indications in solid tumors

Conclusion

The development of PD-1/CTLA-4 bispecific antibodies marks a new stage in immune checkpoint therapy.

From monoclonal antibodies to combination therapies and now bispecific formats, cancer immunotherapy is evolving toward mechanism-based synergy and precision modulation.

In the future, bispecific and multi-target immunotherapy strategies may further improve efficacy in solid tumors such as lung cancer, cervical cancer, and hepatocellular carcinoma, while enabling more refined patient stratification and long-term disease control.