Between 2024 and 2025, Programmed Death-Ligand 1 (PD-L1) targeted therapies have once again become a focal point in global cancer immunotherapy. On one hand, PD-L1 based bispecific antibodies, such as PD-L1xVEGF and PD-L1xCTLA-4, have continued to release encouraging mid to late stage clinical data in lung cancer, hepatocellular carcinoma, and gastric cancer, demonstrating efficacy that may surpass traditional monoclonal antibodies. On the other hand, as first-generation PD-L1 monoclonal antibodies, including Atezolizumab, Durvalumab, and Avelumab, approach patent expiration, pharmaceutical companies worldwide are accelerating efforts toward differentiated innovation.
PD-L1 is no longer viewed merely as a standalone drug target. Instead, it has emerged as a central hub for immune combination therapies and multifunctional molecular designs, fundamentally reshaping the R&D landscape of PD-L1 targeted drugs.
1. Global Landscape of PD-L1 Drug Development
According to clinical trial registries and industry analyses, over 800 PD-L1 related programs (including monotherapies and combination strategies) are currently under development worldwide, involving more than 100 biopharmaceutical companies. These programs span all stages from discovery and preclinical research to Phase III trials and commercialization.
Approximately 500 programs remain in discovery or preclinical stages, 200 have been discontinued or suspended, 130 are in Phase I or II trials, and around 20 have reached Phase III, registration, or market approval (primarily mature monoclonal antibodies and select bispecific formats). Key players include Roche, AstraZeneca, Pfizer, Merck, Akeso, BeiGene, Innovent, and Alphamab Oncology. Therapeutic modalities encompass monoclonal antibodies, bispecific/multispecific antibodies, antibody drug conjugates (ADCs), small-molecule inhibitors, and combination regimens.
2. Progress Across Different PD-L1 Therapeutic Modalities
Current PD-L1 targeted drug development spans five major categories. While monoclonal antibodies remain the largest group, their proportional dominance is gradually declining. Bispecific and multispecific antibodies represent the fastest-growing segment and are becoming the mainstream strategy. PD-L1 ADCs are emerging in early clinical exploration, small-molecule PD-L1 inhibitors offer oral advantages despite high technical barriers, and PD-L1 based combination therapies serve as the backbone of modern immuno-oncology regimens.
2.1 PD-L1 Monoclonal Antibodies
PD-L1 monoclonal antibodies are now a mature and well-established class, with new development primarily focused on combination therapies and lifecycle management. Approved products include Avelumab (Bavencio), Durvalumab (Imfinzi), and Atezolizumab (Tecentriq).
- Avelumab, co-developed by Merck KGaA and Pfizer, was FDAapproved in 2017 for metastatic Merkel cell carcinoma and later expanded to urothelial carcinoma and renal cell carcinoma in combination with axitinib.
- Durvalumab, developed by AstraZeneca, has become a cornerstone therapy in NSCLC and SCLC. In March 2025, the FDA approved its use with gemcitabine and cisplatin for perioperative treatment of muscle-invasive bladder cancer.
- Atezolizumab, developed by Genentech/Roche, was among the first approved PD-L1 inhibitors and remains widely used across multiple solid tumors, often in combination with chemotherapy or anti-angiogenic agents.
2.2 PD-L1 Bispecific and Multispecific Antibodies
PD-L1 bispecific antibodies represent the fastest-growing category, with increasing focus on targets such as VEGF, CTLA-4, TGFβ, and 4-1BB. Leading developers include BioNTech, BMS, Akeso, BeiGene, and Alphamab Oncology.
- Pumitamig (BNT327), a PD-L1xVEGFA bispecific antibody co-developed by BioNTech and BMS, has shown promising efficacy in extensive-stage small cell lung cancer and is advancing into Phase III trials.
- Erfonrilimab (KN046), a PD-L1xCTLA-4 bispecific antibody developed by Alphamab Oncology, is undergoing Phase II/III studies across multiple solid tumors.
- Opamtistomig (LBL-024), a PD-L1x4-1BB bispecific antibody from Nanjing Leads Biolabs, has entered registrational trials with encouraging early efficacy and manageable toxicity.
2.3 PD-L1 ADCs
PD-L1 ADCs aim to combine immune checkpoint blockade with direct cytotoxic delivery, particularly in immunologically “cold” tumors. Although still limited in number, this category is gaining momentum. Key programs include SGN-PDL1V (PF-08046054) and HLX43.
- SGN-PDL1V, originally developed by Seagen and later acquired by Pfizer, is currently in Phase I trials, showing manageable safety and early antitumor activity.
- HLX43, developed by Henlius, has demonstrated preliminary efficacy signals in NSCLC based on Phase I data presented in 2025.
- JSKN022, a first-in-class PD-L1xαvβ6 bispecific ADC from Alphamab Oncology, has entered Phase I clinical studies following IND approval in China.
2.4 Small-Molecule PD-L1 Inhibitors
Small-molecule PD-L1 inhibitors offer oral administration and cost advantages, though structural constraints pose significant challenges. Notable programs include CA-170, INCB086550, BPI-371153, and CS23546.
- CA-170, developed by Aurigene and Curis, is an oral PD-L1xVISTA(B7-H5) inhibitor that has demonstrated immune activation signals in Phase II studies.
- INCB086550 (Incyte) and BPI-371153 (Betta Pharmaceuticals)are advancing through early clinical development.
- CS23546, developed by Chipscreen Biosciences, promotes PD-L1 internalization and has received Phase I trial approval in China.
2.5 PD-L1 Combination Therapy Strategies
PD-L1 inhibitors have become the foundation of modern immunotherapy combinations. The most established approach is PD-L1 plus chemotherapy, which induces immunogenic cell death and enhances antitumor immunity. Regimens such as Atezolizumab plus chemotherapy and Durvalumab plus chemotherapy are now standard first-line treatments in multiple indications.
Combination with anti-angiogenic therapy (VEGF inhibition) further remodels the tumor microenvironment, exemplified by Atezolizumab plus Bevacizumab and PD-L1xVEGF bispecific antibodies. Emerging combinations with ADCs, cancer vaccines, radiotherapy, and cell therapies (TILs, NK cells) emphasize mechanistic synergy and represent the next wave of PD-L1 innovation.
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