Over the past year, the PD-1 immunotherapy landscape has once again witnessed intensive progress. From multiple anti–PD-1 monoclonal antibodies achieving Phase III success in new indications to the rapid emergence of bispecific antibodies and increasingly sophisticated combination regimens that continue to push efficacy boundaries, PD-1–targeted therapies remain firmly positioned at the core of cancer immunotherapy.
This article provides a systematic overview of the global PD-1 development landscape, major drug modalities, and the latest clinical advances, helping readers understand where PD-1 targeted therapies currently stand in the evolving immuno-oncology ecosystem.
1. Global Landscape of PD-1 Targeted Drug Development
According to incomplete statistics, more than 700 PD-1 targeted drug candidates are currently under development worldwide. Overall, the PD-1 pipeline is characterized by a large number of programs, diverse therapeutic modalities, and increasingly globalized development strategies.
To date, 22 PD-1 targeted drugs have been approved globally, including 19 monoclonal antibodies and 3 bispecific antibodies. More than 470 candidates are in the discovery or preclinical stage, while approximately 186 programs have entered clinical development, including 118 in Phase I or Phase I/II trials and 29 in Phase III studies.
Therapeutic modalities span monoclonal antibodies, bispecific and multispecific antibodies, as well as a broad range of combination strategies. Global registration and large Phase III trials are still largely dominated by multinational pharmaceutical companies such as Merck, Bristol Myers Squibb (BMS), Roche, AstraZeneca, and Pfizer. Meanwhile, Chinese and other Asian biotech companies, including Akeso, BeiGene, Junshi Biosciences, Henlius, and Innovent, have demonstrated strong momentum, particularly in bispecific antibody development and region-specific regulatory pathways.
Overall, the PD-1 field is rapidly transitioning from single-drug competition toward multi-modal and differentiated technological strategies.
2. Major PD-1 Targeted Drug Modalities and Recent Progress
PD-1 targeted therapies have expanded beyond traditional monoclonal antibodies to include bispecific/multispecific antibodies, exploratory small-molecule protein–protein interaction (PPI) inhibitors, and extensive combination regimens.
Currently, monoclonal antibodies remain the dominant modality, accounting for approximately 65–70% of all approved and in-development PD-1 programs. Bispecific and multispecific antibodies represent roughly 15–20% of the pipeline and constitute the fastest-growing category in recent years. Combination therapies centered on PD-1 antibodies account for about 10%, while other modalities, including cell therapies, fusion proteins, and therapeutic vaccines, make up the remaining 5%.
Note: Unlike PD-L1, there are currently no clinically traceable antibody–drug conjugates (ADCs) that directly target PD-1. For a detailed comparison between PD-1 and PD-L1 targeting strategies
2.1 PD-1 Monoclonal Antibodies
PD-1 monoclonal antibodies form the foundation of modern cancer immunotherapy. By blocking the interaction between PD-1 receptors on T cells and their ligands (primarily PD-L1), these agents release inhibitory immune signals and restore tumor-specific immune responses. As the earliest immune checkpoint inhibitors to reach the clinic, they continue to represent the backbone of immuno-oncology pipelines. Representative agents include:
- Pembrolizumab (Keytruda®, Merck): First approved by the FDA in 2014 for advanced melanoma, pembrolizumab has since expanded to more than 18 cancer indications, including NSCLC, gastric cancer, MSI-H colorectal cancer, head and neck cancer, and renal cell carcinoma. In March 2025, results from the Phase III KEYNOTE-811 trial demonstrated significant survival benefits when combined with trastuzumab and chemotherapy in HER2-positive gastroesophageal cancer, leading to FDA approval as a first-line regimen.
- Nivolumab (Opdivo®, BMS): Approved shortly after Keytruda, nivolumab has become standard therapy across multiple solid tumors. In 2025, the FDA expanded its first-line indication in combination with ipilimumab for MSI-H/dMMR colorectal cancer, reinforcing its role in both monotherapy and combination settings.
- Cemiplimab (Libtayo®, Regeneron/Sanofi): First approved in 2018 for locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC), Libtayo was the first immune checkpoint inhibitor approved for this indication. Its clinical footprint has continued to expand since then.
In addition, several next-generation PD-1 monoclonal antibodies reported meaningful breakthroughs or data updates in 2025:
- Sasanlimab (PF-06801591, Pfizer): A humanized PD-1 antibody evaluated primarily in non–muscle-invasive bladder cancer (NMIBC). Phase III CREST trial data showed that sasanlimab combined with BCG significantly improved event-free survival compared with BCG alone, suggesting potential to reshape NMIBC immunotherapy standards in high-risk populations.
- Penpulimab (AK105, Akeso): Approved by the FDA in 2025 for non-keratinizing nasopharyngeal carcinoma, marking a milestone for Chinese innovative PD-1 antibodies entering the US market. This approval highlights the growing global registration capabilities of China-origin PD-1 programs.
As the PD-1 monoclonal antibody class matures, development focus is increasingly shifting toward optimized delivery (e.g., subcutaneous administration, long-acting formulations), biomarker-driven patient selection, and rational combination strategies aimed at improving efficacy while reducing immune-related adverse events.
2.2 PD-1 Bispecific and Multispecific Antibodies
PD-1 bispecific antibodies are designed to simultaneously target PD-1 and another immune-regulatory or tumor-associated pathway, such as VEGF, CTLA-4, or IL-2α, within a single molecular entity, enabling synergistic immune activation and tumor microenvironment remodeling.
Approved examples include Ivonescimab (PD-1xVEGF) and Cadonilimab (PD-1xCTLA-4), both developed by Akeso and approved in China for recurrent/refractory cervical cancer and advanced or metastatic non-squamous NSCLC, respectively. These approvals mark the transition of PD-1 bispecific antibodies from early clinical exploration into real-world therapeutic use. Notable PD-1 bispecific/multispecific antibodies with key progress in 2025 include:
- LM-299 (LaNova Medicines): A PD-1xVEGF bispecific antibody currently in Phase I clinical evaluation in China for solid tumors.
- CR-001 (Crescent Biopharma):A PD-1xVEGF bispecific antibody featuring a novel tetravalent architecture, with Phase I/II trials planned to initiate in 2026.
- BI363 (Innovent): A PD-1–targeting antibody with IL-2α bias, which presented encouraging early signals across melanoma, colorectal cancer, and NSCLC at ASCO 2025.
- CS2009 (CStone Pharmaceuticals): A PD-1xVEGFAxCTLA-4 trispecific antibody designed to integrate immune checkpoint blockade, anti-angiogenesis, and T-cell activation. Initial Phase I data presented at ESMO 2025 demonstrated manageable safety. Phase II multi-cohort studies are now underway globally.
In parallel, PD-1/VEGF bispecific antibodies have become a hot area for business development. Notably, BioNTech and BMS entered a strategic collaboration valued at up to USD 11 billion to co-develop dual-target antibodies such as BNT327 (PD-L1xVEGF), underscoring strong industry confidence in this modality.
2.3 Combination Strategies: PD-1 Plus Multi-Modal Synergy
Combination therapy has become a central strategy in PD-1 drug development, aiming to overcome the limitations of single-agent immune checkpoint blockade and improve response rates.
Representative approaches include PD-1 plus CTLA-4 dual checkpoint inhibition, PD-1 combined with chemotherapy or targeted therapies, and PD-1 paired with novel immune modulators. Examples include nivolumab plus ipilimumab in MSI-H/dMMR colorectal cancer, pembrolizumab plus trastuzumab and chemotherapy in HER2-positive gastric cancer, and Replimune’s RP1 oncolytic virus combined with nivolumab in advanced melanoma.
These combinations continue to be validated through Phase III trials and are expanding the population of patients who may benefit from PD-1 based immunotherapy.
2.4 Other PD-1–Targeted Therapeutic Approaches
Beyond antibodies, innovative strategies targeting the PD-1 pathway are also being actively explored, including cell therapies, fusion proteins, and therapeutic vaccines. These approaches aim to overcome resistance and enhance immune activation in low-response tumors.
Cell therapy represents a key area of innovation. For example, Beijing Tykamed (TianKeya) is developing engineered T-cell products capable of secreting anti PD-1 antibody components or incorporating immune checkpoint blockade mechanisms. TC-E202, a TCR-T therapy loaded with anti–PD-1 single-chain antibodies, is under clinical evaluation for HPV-positive recurrent or metastatic cervical cancer.
Fusion proteins are another important direction. Innovent’s IBI363, a first-in-class PD-1/IL-2α–biased bispecific fusion protein, has demonstrated promising safety and efficacy signals in Phase I/II studies across China, the US, and Australia, earning FDA Fast Track designation and NMPA Breakthrough Therapy status.
Similarly, TQB2868 from Chia Tai Tianqing is a PD-1/TGF-β dual-function fusion protein that has shown encouraging Phase II results in metastatic pancreatic ductal adenocarcinoma and has advanced into global Phase III trials.
Overall, while most non-antibody PD-1–targeted approaches remain in early clinical development, they represent a broader shift from single antibodies toward intelligent cell therapies and multifunctional molecules, with the potential to further expand the therapeutic reach of PD-1 immunotherapy.
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