PD-1 Antibody Development Programs for Cancer Immunotherapy

The infusion room is colder than expected. A plastic wristband presses against the patient’s skin. Across the room, a pump clicks at steady intervals like the wall clock. Infuriating precision. The patient’s palms leave damp marks on the arms of the chair. On the phone beside them is a message from home asking how things are going. There is no useful answer. The last CT scan showed that the cancer was still there, still growing after previous treatment. Chemotherapy has already had its chance.

Now a gloved nurse connects a clear bag to the intravenous line. Inside is an antibody that will not poison the tumor, cut off its DNA replication, or directly kill a single malignant cell. Instead, it will attempt something more audacious: remove a molecular brake from the patient’s own immune system and ask T cells to finish the job.

There is no way, as the infusion begins, to know whether they will.

That uncertainty sits at the heart of every oncologic drug development program. Immune checkpoint blockade has transformed the treatment of multiple cancers, producing responses that can sometimes remain durable for years. But many patients never respond, others relapse after an initial response, and some unlucky guys develop severe immune-mediated toxicity. The therapeutic opportunity is enormous precisely because the unfinished work is enormous.

Worldwide, an estimated 20.6 million people were diagnosed with cancer in 2024 and approximately 9.8 million died from it, according to the latest GLOBOCAN estimates reported by the International Agency for Research on Cancer.¹

The infusion pump continues to tick.

Editorial note: the patient scene above is a composite created to represent experiences common in oncology care; it does not describe an identifiable individual.

The Most Important Oncologic Therapeutic Target

Calling any single molecule the most important therapeutic target in oncology is deliberately provocative. Cancer is not one disease, and no molecular pathway dominates every malignancy.

Yet PD-1 has an unusually strong claim. A PD-1 antibody is not primarily attacking the malignant cell’s machinery. It is attempting to change the conversation between the tumor and the immune system.

PD-1 Discovery

The story started in Kyoto in 1992.

Yasumasa Ishida, Yasutoshi Agata, Keiichi Shibahara and Tasuku Honjo were studying genes associated with programmed cell death when they isolated a previously unknown member of the immunoglobulin superfamily. They named it programmed cell death protein 1. PD-1. At the time, its future role in cancer therapy was far from obvious.²

The interpretation soon changed.

Experiments showed that PD-1 appeared on the surface of activated lymphocytes rather than functioning simply as a molecular execution switch. In 2000, Lieping Chen, Gordon Freeman, and Tasuku Honjo laboratories identified independently PD-L1 as a ligand for PD-1 and demonstrated that engagement of the receptor inhibited T-cell proliferation and cytokine production.^3,4 A second ligand, PD-L2, was characterized the following year.⁵

Then came the experiment that helped turn an immunological curiosity into an oncology strategy.

In 2002, Yoshiko Iwai, Honjo and colleagues engineered tumor cells to express PD-L1. Those tumors became more resistant to T-cell-mediated destruction and more aggressive in mice. Blocking PD-L1 reversed the effect. The paper concluded that PD-L1 could serve as a mechanism allowing immunogenic tumors to escape host immunity and that interruption of the PD-1/PD-L interaction could provide a strategy for cancer immunotherapy.⁶ The target had acquired a purpose.

Structure of PD-1 and its ligands

At the molecular level, PD-1 is surprisingly economical. It is a single-pass transmembrane receptor. Outside the T cell sits an immunoglobulin variable-like, or IgV, domain – the part that meets its ligands. A membrane-spanning segment anchors the receptor. Inside the cell, the cytoplasmic tail contains signaling motifs, including an immunoreceptor tyrosine-based inhibitory motif, or ITIM, and an immunoreceptor tyrosine-based switch motif, or ITSM, that allow extracellular contact to be translated into intracellular inhibition.^7,8

Fig. 1. Molecular structure of PD-1 and its interaction with ligands PD-L1 and PD-L2.⁹

Structural studies show the extracellular PD-1 domain adopting the characteristic β-sandwich architecture of an IgV-family protein. When PD-1 meets PD-L1, their IgV domains form a 1:1 complex with an interface reminiscent of the variable-domain pairing seen in antibodies and antigen receptors.⁹

PD-L1 is itself a membrane protein. Its extracellular region contains an N-terminal IgV-like domain that contacts PD-1 and an IgC-like domain closer to the membrane.¹⁰ PD-L2 follows a related architecture.¹¹ But knowing the structure is only the beginning. The reason pharmaceutical developers care about the receptor becomes apparent when the interaction is followed one event at a time.

Cancer presses the PD-1 brake

The PD-1 pathway acts as an immune checkpoint brake that prevents T-cells from attacking normal cells. Cancer cells exploit this system by displaying PD-L1, which binds to PD-1 on T-cells, deactivating them and hiding the tumor from the immune system.

Fig. 2. Brakes and accelerators control immune reactions like those in a car.¹²

The T cell recognizes danger. Tumor-derived peptide presented in an MHC molecule engages the T-cell receptor. Costimulatory signaling, particularly through receptors such as CD28, helps determine whether the T cell becomes fully activated.
Activated T cells can increase PD-1 expression. This is physiologically useful. The immune system needs mechanisms that stop inflammatory responses from continuing indefinitely.
PD-L1 or PD-L2 encounters PD-1. PD-L1 can be expressed by immune cells and by malignant cells, and inflammatory signaling in the tumor microenvironment can increase its expression. PD-L2 also binds PD-1 and can suppress T-cell responses.
PD-1 engagement leads to phosphorylation cascade at T cell cytoplasmic signaling motifs and recruitment of phosphatases including SHP proteins, with SHP-2 playing a prominent role in the inhibitory signaling complex.¹³
Activating pathways are dampened. Signals generated by the T-cell receptor and costimulatory machinery are weakened. T-cell proliferation falls. Cytokine production decreases. The cell becomes less effective at maintaining an attack. Freeman and colleagues demonstrated precisely this inhibitory effect on TCR-mediated proliferation and cytokine secretion in their early ligand studies.
Finally, the tumor gains time. In a chronic tumor environment, where antigen exposure may continue for months or years, repeated inhibitory signaling can contribute to a dysfunctional immune state. A malignant cell carrying PD-L1 does not need to become invisible; it can remain visible while making the attacking T cell progressively less effective. Experimental work demonstrating PD-L1-driven tumor escape provided the crucial bridge between this biology and therapeutic intervention.

Fig. 3. Regulatory mechanisms of PD-1/PD-L1 in cancers.¹⁴

Cancer has, in effect, discovered the password to an immune safety system.

PD-1 as a drug target

PD-1 is accessible on the cell surface, making it suitable for recognition by therapeutic antibodies. Its ligands have a demonstrable role in immune suppression. Animal experiments showed that interference with the pathway could restore antitumor activity. And, critically, PD-1 sits on immune cells rather than being restricted to a mutation found in one particular cancer.¹⁵

That created the possibility of a cross-tumor therapeutic platform. The main question is: Is there an antitumor immune response here that is being restrained? If the answer is yes, the tissue of origin may become less decisive.

That is also the source of the risk. PD-1 exists because immune restraint is physiologically necessary. Early experiments showed that disrupting the pathway could break peripheral tolerance and produce autoimmune phenomena. Modern clinical experience confirms the other side of checkpoint blockade: releasing immune inhibition can also allow immune cells to damage normal tissues.¹⁶

Anti PD-1 and Anti PD-L1 Therapeutic Antibodies

The translation of this target from bench to clinical practice yielded revolutionary therapies that represent the gold standards of modern immunotherapy. Developing such a medicine starts long before a patient enters a clinical trial. The research team first needs antibodies that recognize the intended target with sufficient specificity. Candidates are screened not merely for binding but for their ability to interfere with the relevant ligand-receptor interaction. Epitope matters. Affinity matters. Functional blockade matters.

Candidates also have to survive decisive realities of biological drug development. They need acceptable stability, aggregation behavior and gene expression. Their manufacturing process must be reproducible. Analytical methods must monitor identity, purity, structure and potency. A functional potency assay must eventually connect a manufactured batch of protein back to the mechanism that made the molecule worth developing.¹⁷

Only after preclinical pharmacology and toxicology can the antibody enter human testing. Phase I studies establish initial safety, exposure and dose or regimen. Expansion cohorts begin looking for tumors in which biological activity is visible. Biomarker programs ask whether PD-L1 expression or another characteristic enriches for response. Randomized trials then force the drug to compete against the existing standard. However, the following years brought successes for PD-1 therapy. The strategy adopted by the scientists yielded results in clinical trials.

Fig. 4. Timeline of anti-PD-1 therapeutic antibodies approvals by regulatory agencies worldwide.

Pembrolizumab – pharmaceutical giant

Before the name Keytruda became globally recognizable, pembrolizumab was MK-3475. It is a humanized IgG4/kappa monoclonal antibody that inhibits interactions between PD-1 and PD-L1/PD-L2. Its first clinical protocol, Study 3475-001 entered the investigational new drug process in December 2010 as a Phase I dose-finding, safety and tolerability study. The protocol was repeatedly amended as evidence accumulated, expanding into tumor cohorts and exploring biomarkers.

On September 4, 2014, the FDA granted accelerated approval for patients with unresectable or metastatic melanoma after progression on prior therapy. In the population supporting the application, the objective response rate at the recommended regimen was approximately 24%, with durability of response helping justify accelerated approval.¹⁸ What followed changed expectations far beyond melanoma.

In KEYNOTE-024 clinical trials, previously untreated patients with metastatic non-small-cell lung cancer (NSCLC) whose tumors expressed PD-L1 at a tumor proportion score of at least 50% were randomized to pembrolizumab or platinum-based chemotherapy. With approximately five years of follow-up, median overall survival was 26.3 months with pembrolizumab versus 13.4 months with chemotherapy. Estimated five-year overall survival was 31.9% versus 16.3%, despite substantial crossover from chemotherapy to subsequent checkpoint therapy.¹⁹

Fig. 5. Kaplan-Meier estimates of overall survival in the pembrolizumab group and the chemotherapy group.¹⁹

Read these figure not as percentages for a moment, but as people. Patients entered that study with metastatic lung cancer. Five years later, almost one-third of those initially allocated to pembrolizumab were still alive.

Structural study has directly visualized a 1:1 PD-1/Fab complex and shown how antibody occupancy prevents the normal receptor-ligand interaction. With PD-L1 and PD-L2 unable to engage PD-1 normally, the inhibitory signaling sequence is reduced.²⁰

Nivolumab – checkmate for melanoma

Nivolumab reached the US market only months after pembrolizumab. The FDA approved Opdivo on December 22, 2014 for previously treated unresectable or metastatic melanoma.

This medicine would soon become part of one of the most consequential long-term experiments in modern melanoma therapy. The ten-year analysis of CheckMate 067 gives unusual perspective on what checkpoint inhibition changed. Among patients with previously untreated advanced melanoma, median overall survival reached 36.9 months with nivolumab monotherapy, compared with 19.9 months for ipilimumab alone. Nivolumab plus ipilimumab pushed median overall survival to 71.9 months. Perhaps the most arresting statistic appears later in the curve. Among patients who were alive and progression-free three years after treatment began, ten-year melanoma-specific survival was 97% in the nivolumab monotherapy group. That statistic applies to a selected subgroup demonstrates how durable successful immune control can become.²¹

Fig. 6. Kaplan-Meier estimates of OS in the nivolumab group and the ipilimumab group.²¹

Before immune checkpoint therapy, metastatic melanoma was commonly approached as a disease in which long-term survival was exceptional. Now oncologists can show selected patients ten-year data.

PD-1 Antibody Development Programs Commercial Impact

The market consequences have been almost as dramatic as the clinical ones.

Keytruda provides the clearest example. Its annual sales rose from approximately $566 million in 2015 to $31.68 billion for Keytruda in 2025. In 2025 alone, the franchise represented almost half of Merck‘s $65.0 billion in total sales. Adding the annual Keytruda sales publicly disclosed for 2015 through 2025 produces approximately $162.7 billion in cumulative sales by calculation.²²

Opdivo remains another multibillion-dollar franchise. Bristol Myers Squibb reported $9.009 billion in 2023, $9.304 billion in 2024 and $10.049 billion in 2025 for Opdivo.²³

These numbers changed the economics of oncology R&D. PD-1 became not simply a validated target but the commercial center of one of the pharmaceutical industry’s largest therapeutic franchises.

Bispecific PD-1 Antibody for Dual Checkpoint Blockade

A tumor exposed to one immune pressure may rely on another suppressive pathway. T cells that escape PD-1 inhibition may still encounter other inhibitory mechanisms. Meanwhile, abnormal tumor vasculature, signaling pathways and other features of the tumor microenvironment can continue to impede immune attack.

The next generation of checkpoint inhibitors aims to block PD-1 with a single molecule and simultaneously limiting cancer escape factors. That is the rationale behind PD-1/PD-L1 bispecific antibody development. But an important distinction is necessary. Some of these molecules are genuine dual-checkpoint inhibitors. Others combine checkpoint inhibition with a different tumor-promoting pathway. They belong to the same engineering wave, but not to exactly the same biological category.

Cadonilimab – PD-1×CTLA-4

Cadonilimab was the first major proof that a dual-checkpoint bispecific could move beyond clinical experimentation into routine marketing. The antibody targets PD-1 and Cytotoxic T Lymphocyte-Associated Antigen-4 (CTLA-4), two inhibitory checkpoints operating at different points in T-cell regulation. In conceptual terms, the molecule attempts to release two brakes with one therapeutic construct.

One binding specificity interferes with PD-1-mediated inhibition. The other attacks CTLA-4-mediated restraint. Rather than administering two separate checkpoint antibodies, developers can attempt to build both functions into one protein architecture and potentially tune how those activities are delivered. That does not automatically guarantee a better therapeutic index. Dual-checkpoint blockade can increase immune toxicity as well as efficacy. The development challenge is not merely to combine mechanisms, but to combine them in a way that improves the benefit-risk equation.

China’s NMPA first approved cadonilimab in June 2022 for recurrent or metastatic cervical cancer progressing on or after platinum chemotherapy.²⁴ In September 2024, approval expanded to first-line locally advanced unresectable or metastatic gastric/gastroesophageal-junction adenocarcinoma in combination with fluoropyrimidine- and platinum-based chemotherapy.²⁵ In 2025, another first-line approval followed for persistent, recurrent or metastatic cervical cancer combined with platinum-based chemotherapy, with or without bevacizumab.²⁶ Cadonilimab’s international development is continuing. By late 2025, the FDA had cleared a global Phase III first-line gastric cancer trial comparing a cadonilimab regimen with nivolumab-based treatment.

Ivonescimab – PD-1×VEGF

Ivonescimab may represent an even more disruptive experiment. It targets PD-1 and Vascular Endothelial Growth Factor (VEGF). Strictly speaking, this is not dual checkpoint blockade. VEGF is an angiogenic and immunomodulatory factor rather than an immune checkpoint receptor. The development logic, however, is closely related: combine two biologically complementary mechanisms in a single antibody.

One arm of the strategy removes PD-1-mediated inhibition. The VEGF-directed component is intended to interfere with a pathway that drives abnormal tumor angiogenesis and contributes to an immunosuppressive tumor microenvironment. Rather than giving an anti-PD-1 antibody and an anti-VEGF therapy as separate drugs, ivonescimab attempts to integrate both functions into one engineered molecule.

In the randomized Phase III study conducted in China, 398 patients with previously untreated, PD-L1-positive advanced NSCLC received either ivonescimab or pembrolizumab. Median progression-free survival was 11.1 months with ivonescimab versus 5.8 months with pembrolizumab.^27,28 That bispecific antibody had defeated one of oncology’s most successful drugs on the primary endpoint of a randomized Phase III head-to-head trial. Ivonescimab is already marketed in China for NSCLC settings, with additional indications subsequently approved. On August 12, 2026, Akeso announced Chinese approval of ivonescimab plus chemotherapy for first-line squamous NSCLC. The geographical context matters, and international validation remains essential. Outside China, the story is still being written. The FDA accepted Summit Therapeutics’ BLA for ivonescimab plus chemotherapy in EGFR-mutated, locally advanced or metastatic nonsquamous NSCLC after EGFR-TKI therapy in January 2026. The FDA assigned a November 14, 2026 PDUFA goal date.

Conclusion

The infusion bag is almost empty now.

The nurse disconnects the line. The patient pulls down a sleeve, collects a coat and walks out through the automatic hospital doors.

Nothing looks different yet.

Inside the body, however, millions of molecular interactions are beginning. Antibody molecules encounter PD-1. T cells receive different signals. Some may move deeper into tumor tissue. Some may recognize malignant cells they had previously been unable to attack effectively.

After decades of development, the challenge is to make that fight work for a much larger fraction of the people sitting in infusion rooms wondering whether another treatment will buy them months, years or the chance to hear that the next scan shows no cancer at all. New indications and concentrations of drugs currently in development or on the market, as well as new antibody formats, are being investigated.^29,30 The scientific race around PD-1 therefore continues. Because somewhere, while those programs advance through discovery laboratories, bioreactors, analytical assays and clinical development, another infusion pump is ticking.

Prepared by:

Jakub Knurek

Marketing Specialist

j.knurek@mabion.eu

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