Cancer’s ability to blunt immune surveillance is central to its persistence. The PD‑1 receptor is upregulated on activated T cells as a physiological brake to prevent autoimmunity; tumours exploit this mechanism by overexpressing PD‑L1 in response to inflammatory cues such as interferon‑γ. Engagement of PD‑1 by PD‑L1 initiates intracellular signalling that reduces T‑cell receptor signalling, proliferation, cytokine production, and cytotoxic function. The result is a state of functional exhaustion inside the tumour microenvironment, characterised by metabolic stress, competing inhibitory receptors such as CTLA‑4, LAG‑3 and TIGIT, and a milieu rich in suppressive myeloid cells and regulatory T cells. Historically, oncology addressed tumour burden with surgery, radiation, chemotherapy, and targeted inhibitors focused on tumour‑intrinsic alterations. While these approaches remain indispensable, their limitations systemic toxicity, resistance, and a lack of durable immune memory left significant unmet need in advanced disease.

Checkpoint blockade provided an elegant external solution by tipping the balance towards immune activation rather than directly poisoning or starving cancer cells. PD‑1 or PD‑L1 antibodies prevent the inhibitory contact, restoring T‑cell function and, in responsive patients, generating long‑lived anti‑tumour memory. Nonetheless, only a subset of patients achieve durable benefit. Primary resistance may reflect low tumour antigenicity or scarce T‑cell infiltration, while acquired resistance may emerge through loss of antigen presentation, upregulation of alternative checkpoints, reprogramming of the myeloid compartment, or interference with interferon signalling. Clinically, the field has also learned to recognise and manage immune‑related adverse events autoimmune‑like toxicities that can affect skin, gut, lung, endocrine organs, and other systems through corticosteroids and, where necessary, additional immunosuppression without fully abrogating anti‑tumour efficacy. The persistence of variable responses, safety considerations, and economic pressures has driven the search for improved modalities, rational combinations, and precision biomarkers.

The approved portfolio of PD‑1 and PD‑L1 inhibitors has matured into a core component of standard of care across multiple malignancies. Pembrolizumab and nivolumab, both PD‑1‑targeting IgG4 antibodies, established proof of concept in melanoma and non‑small cell lung cancer before expanding to urothelial carcinoma, renal cell carcinoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, classical Hodgkin lymphoma, endometrial cancer with mismatch‑repair deficiency, and others. PD‑L1‑targeting antibodies such as atezolizumab, durvalumab, and avelumab added breadth, with clinical nuances stemming from differences in isotype and Fc‑mediated effector function. Over time, label expansions moved these medicines into earlier lines, perioperative settings, and combination regimens, reflecting improved survival and tolerability compared with historical standards.

Beyond antibodies, the late‑stage pipeline includes subcutaneous formulations for administration convenience; Fc‑modified constructs designed for tailored effector profiles; bispecifics co‑blocking PD‑1 and another checkpoint; tumour‑targeted T‑cell engagers that incorporate a PD‑1/PD‑L1 arm; and small‑molecule or peptide antagonists that promise oral dosing. Parallel advances in companion diagnostics—especially refined PD‑L1 immunohistochemistry scoring, tumour mutational burden quantification, and MSI/dMMR testing have become integral to treatment selection in several tumour types. Clinical practice has evolved to manage immune‑related adverse events proactively, employ steroid‑sparing strategies when possible, and continue therapy judiciously through low‑grade toxicities that are manageable without compromising long‑term benefit. In real‑world oncology, these products are now frequently combined with chemotherapy, anti‑angiogenic agents, or targeted inhibitors, with the intent of converting transient cytoreduction into durable immune control.

Leadership in the PD‑(L)1 space reflects a blend of first‑mover advantage, sustained clinical development, manufacturing sophistication, and strategic partnering. Large, research‑intensive biopharmaceutical companies have dominated originator development of antibodies, while a robust ecosystem of biotechnology firms explores next‑generation modalities and combinations. Merck & Co. leveraged pembrolizumab’s early successes into a sweeping clinical program that continually expanded indications and reinforced market leadership. Bristol Myers Squibb built an extensive immuno‑oncology franchise around nivolumab and combination strategies, particularly with CTLA‑4 inhibition. Roche/Genentech advanced PD‑L1‑targeting atezolizumab and integrated it with a deep diagnostics capability through affiliated businesses, illustrating the value of pairing therapeutics with precision medicine tools. AstraZeneca’s durvalumab program moved decisively into lung cancer consolidation therapy and other settings, while Pfizer and partners extended avelumab into niches where its effector function may be advantageous.

In parallel, several China‑originated companies have developed domestically approved PD‑1 antibodies and are increasingly integrating into global development through ex‑China trials and partnerships. Differentiation today often resides less in “another PD‑(L)1 antibody” and more in the sophistication of combination regimens, the quality and speed of clinical execution, the robustness of safety‑management infrastructure, and the breadth of diagnostic and digital support that ensures patients most likely to benefit are identified and treated efficiently. Manufacturing scale, formulation innovation, and lifecycle strategies such as subcutaneous delivery or long‑acting dosing also shape competitive positions.

Three interlocking research themes dominate contemporary scholarship. The first is the pursuit of rational combinations. Investigators are mapping how radiotherapy, selected chemotherapies, targeted agents against oncogenic drivers, and anti‑angiogenic drugs remodel the tumour microenvironment in ways that synergise with checkpoint blockade. Trials increasingly use translational endpoints serial biopsies, circulating tumour DNA dynamics, and immune‑PET imaging to test mechanistic hypotheses rather than relying solely on clinical outcomes long after. The second theme is the expansion and refinement of biomarkers. Although PD‑L1 immunohistochemistry remains widely used, quantitative thresholds and scoring algorithms vary across tumour types and assays. Research programmes now incorporate tumour mutational burden, mismatch‑repair status, interferon‑γ‑associated gene signatures, T‑cell receptor clonality, and spatial metrics that capture where and how immune cells interact with cancer cells within tissue architecture.

Advances in machine learning applied to digital pathology promise standardisation and richer predictive power. The third theme is modality innovation. Structure‑based drug design has delivered macrocyclic and small‑molecule inhibitors capable of perturbing the PD‑1/PD‑L1 binding interface, while chemical biology explores covalent and allosteric strategies to tilt signalling back towards activation. Bispecifics and tethering strategies are being tuned to concentrate activity in tumours while sparing healthy tissues, and nanoparticle systems are being configured to co‑deliver checkpoint antagonists with immune stimulants or with antigens to convert tumours into in situ vaccines. Across all themes, an emphasis on understanding and overcoming resistance particularly through manipulation of the myeloid compartment, metabolic constraints, and stromal barriers remains paramount.

The intellectual‑property landscape around PD‑1 and PD‑L1 inhibitors is both mature and dynamic. Foundational patents protect therapeutic antibodies, epitope and binding characteristics, methods of treatment across tumour types, and manufacturing processes and formulations. As markets globalised, families were extended across the United States, Europe, Japan, and China with strategic use of patent term extensions to align with biologic approval timelines. Subsequent layers of patenting have focused on specific antibody variants with tuned Fc backbones, subcutaneous and high‑concentration formulations, and fixed‑dose combinations. In parallel, method‑of‑treatment claims increasingly reference biomarker‑defined subpopulations, such as high PD‑L1 expressers, MSI‑high tumours, or high tumour mutational burden cohorts, reflecting a tight coupling between diagnostics and therapeutics.

New entrants have sought white space in alternative modalities: macrocyclic peptides and small molecules that inhibit PD‑1/PD‑L1 interaction, bispecific formats co‑targeting checkpoints or tumour antigens, and imaging agents that quantify target expression in vivo. Top patent holders include originator companies responsible for the leading antibodies, along with diagnostics firms and academic institutions contributing to biomarker and imaging advances. For developers, freedom‑to‑operate increasingly hinges on careful mapping of claim scope around epitopes, combinations, and dosing regimens, and on building portfolios that protect not only a molecule but the clinical context and delivery innovations that make it useful in practice.

Patent Landscape Insights & Strategic Implications

• Modality diversification matters: The shift from antibody therapeutics toward macrocycles, small molecules and multispecific constructs is clearly patent-protected (e.g., EP3943083A1, US20140294898A1). This signals that future competitive differentiation will hinge on non-antibody formats, and patent portfolios must cover these.
• Combination claims are critical: Patents increasingly protect combinations (e.g., antibody + small molecule; checkpoint inhibitor + chemo/radiotherapy) and methods of co-administration (US20200407448A1). For a new entrant, clearing combination claims is as important as the core inhibitor claim.
• Delivery & formulation improvements still valuable: Antibody patents continue to claim improved effector function (ADCC/CDC), fragment engineering, dosing forms, subcutaneous versions (US12,391,758). Thus lifecycle extension and manufacturing/format innovation remain patentable and commercially important.
• Global coverage and geographic strategy: With filings in the US, Europe, China, the patent holders are pursuing broad geographies. The sheer volume (~5,000 patents) means freedom-to-operate (FTO) is complex and must address multiplicity of jurisdictions.
• Diagnostics/biomarkers included: Although not detailed here, many patent families relate to methods of patient selection, biomarker assays (PD-L1 IHC, TMB), and imaging. These are increasingly integrated with therapeutics claims.
• Patent expiry and lifecycle planning: Many original antibodies are near patent expiry in some jurisdictions; however, the improvement patents (formats, combinations) may extend exclusivity. New developers must map when core claims expire and what secondary patents remain.
• Emerging white space: The reviews indicate recent wave of small-molecule/macrocyclic filings (post-2020) focusing on overcoming limitations of antibodies (cost, delivery, tumour penetration). For India/Asia-Pacific players, this may represent an opportunity to launch generics or biosimilars if core patents expire, but must still navigate newer coverage.

Patent Filing Trends for PD-1/PD-L1 Inhibitors (Last 10+ Years)

The patent landscape for PD-1/PD-L1 inhibitors, which are a breakthrough in cancer immunotherapy, has seen a significant surge, particularly since the first drug approvals around 2014.

• Overall Trend: The total number of published patents and patent applications related to PD-1/PD-L1 inhibitors has been increasing rapidly. As of a few years ago, the number of published patents was estimated to be around 5,000 and continues to grow.
• Period of Peak Growth (Approx. 2010 onwards): The period following the key discoveries and initial clinical success (especially after 2014) saw an “explosive” growth in patent filings as companies focused heavily on developing new antibodies, small molecules, bispecifics, combination therapies, and new formulations/uses (known as “evergreening” strategies).
• Current Focus: Recent patent filings (2022-present) show a strong focus on:
  • Small-molecule inhibitors and macrocyclic peptides as alternatives to traditional monoclonal antibodies.
  • Combination therapies (e.g., with other cancer treatments or other immune checkpoint inhibitors).
  • Next-generation therapeutics like PROTAC degraders, and novel formulations (e.g., subcutaneous).

Top 10 Assignees (Top Players/Companies)

The patent landscape is dominated by large pharmaceutical companies that developed the first-in-class drugs, along with significant contributions from others in next-generation molecules and novel methods of use.

Top 10 Countries for Patent Filings

Patent filings generally follow market size and R&D investment. For this field, the patent systems in the countries/regions with the largest pharmaceutical markets and robust biotech sectors are the most important.

Innovation in PD‑(L)1 therapeutics has been geographically concentrated in regions with dense biopharmaceutical ecosystems, supportive regulators, and robust clinical‑trial networks. The United States remains the dominant hub for discovery, early‑phase clinical development, and many pivotal trials, supported by academic cancer centres and an extensive community‑oncology network. Europe, including the United Kingdom, Germany, France, Italy, and the Nordics, contributes substantial basic immunology and translational research and hosts numerous multi‑country trials that inform regulatory and reimbursement decisions across heterogeneous health systems. Japan has played an outsized role in precision oncology and immune‑related safety management, informing best practices in perioperative and adjuvant settings. China has rapidly scaled immuno‑oncology capabilities, with domestic PD‑1 inhibitors approved locally and an expanding footprint in global multicentre trials; a growing cadre of biotech firms now originates assets and conducts ex‑China development through partnerships.

In the broader Asia‑Pacific, South Korea and Singapore offer high‑quality trial infrastructure, while India is emerging as a strategic site for late‑phase trials, pharmacovigilance, and cost‑efficient biologics manufacturing. Latin America and the Middle East are increasingly included in multinational studies, improving representativeness and access. From an IP and market‑access perspective, coverage across the United States, Europe, Japan, and China remains essential, while manufacturing and clinical operations in India and Southeast Asia can provide meaningful cost and speed advantages for scale.

Looking ahead, checkpoint inhibition is poised to deepen its role in oncology while evolving meaningfully in format, delivery, and precision. As biomarker science matures, treatment decisions will rely less on single‑analyte thresholds and more on composite, spatially resolved signatures that capture the dialogue between immune cells and cancer. Imaging of PD‑(L)1 expression and T‑cell activation, through immuno‑PET and functional modalities, may shift response assessment from late surrogate endpoints to earlier, actionable readouts. Modality diversification is likely to introduce oral or subcutaneous small‑molecule antagonists and long‑acting antibody formulations that improve patient convenience and lower system costs. Bispecific and multispecific designs may enable more potent yet selective activity by synchronising checkpoint release with tumour engagement. On the systems side, real‑world evidence, federated learning across cancer centres, and adaptive platform trials should accelerate iteration towards the most effective combinations for each biological context. For health systems and payers, pressure to demonstrate cost‑effectiveness will motivate narrower, biomarker‑defined use and value‑based arrangements, while originators will extend lifecycles through new settings and delivery innovations. In emerging markets, biosimilar development and technology transfer will expand access, and domestic innovation in diagnostics will localise precision‑oncology pipelines. Risks remain, including resistance mechanisms that erode durability, immune toxicities that complicate chronic use, and competition from novel modalities such as engineered cellular therapies. Yet the balance of evidence suggests that the PD‑(L)1 axis will remain a backbone of immuno‑oncology for the next decade, both as monotherapy in select biomarker groups and as a partner in rational combinations for the broader population.

The PD‑1/PD‑L1 checkpoint pathway has transformed oncologic care by re‑enlisting the patient’s immune system as a durable weapon against cancer. The technology landscape today reflects a mature first wave of antibodies augmented by a second wave of innovations that aim to increase the breadth and depth of clinical benefit while simplifying delivery and improving access. Competitive advantage is shifting towards companies that integrate therapeutics with diagnostics, master combination science, and execute global development with operational excellence. From an intellectual‑property perspective, freedom‑to‑operate now requires sophistication across modalities, methods of treatment, and delivery systems. Geographically, while the United States, Europe, Japan, and China remain central, manufacturing, clinical operations, and market expansion across the broader Asia‑Pacific—including India—are becoming strategically valuable. For decision‑makers, the actionable imperatives are clear: invest in biomarker‑driven development, build or partner for diagnostic and imaging capabilities, pursue combinations grounded in tumour‑immune biology, and design portfolios that anticipate lifecycle management and global access from the outset. Stakeholders that execute on these principles will be best positioned to deliver meaningful patient outcomes and durable enterprise value in the evolving PD‑(L)1 era.