4-1BB antibodies are a form of cancer immunotherapy designed to enhance the body’s immune system to fight malignant cells. These therapeutic agents are under investigation in numerous clinical trials to establish their safety and effectiveness in treating various cancers and providing a durable anti-tumor response.
The 4-1BB Pathway and Antibody Mechanism
The 4-1BB protein, also known as CD137, is a co-stimulatory molecule from the tumor necrosis factor receptor superfamily. It becomes expressed on the surface of T-cells and natural killer (NK) cells after they are activated by encountering a cancer cell. This molecule acts as an accelerator for these immune cells, providing signals that boost their ability to multiply, survive, and destroy targeted cells. The natural partner for 4-1BB is a ligand called 4-1BBL, found on specialized antigen-presenting cells.
The interaction between 4-1BB and its ligand is a normal part of a healthy immune response. Therapeutic 4-1BB antibodies are engineered to artificially trigger this pathway and are known as agonist antibodies, meaning they stimulate the natural signaling process. By binding to the 4-1BB receptor on activated T-cells, these antibodies enhance the T-cells’ anti-tumor capabilities.
This stimulation encourages the proliferation of CD8+ T-cells, the primary “killer” cells of the immune system, and helps them survive longer to fight the cancer. The signaling also increases the production of pro-inflammatory cytokines like interferon-gamma, which further supports a robust immune attack.
Two of the first-generation 4-1BB agonist antibodies to enter clinical trials were urelumab and utomilumab. Urelumab binds to the receptor without interfering with the natural ligand, 4-1BBL, leading to a very strong, or super-agonistic, signal. In contrast, utomilumab binds to a different site and competes with the natural ligand, resulting in a weaker signal. These distinct binding mechanisms have led to different outcomes in clinical studies regarding both effectiveness and side effects.
Objectives of Clinical Trials
The primary goals of clinical trials for 4-1BB antibodies are to determine a safe dosage and measure the treatment’s effectiveness. Early-phase trials, often using a “3+3” dose-escalation design, focus on safety. In this design, small groups of patients receive increasing doses to identify the maximum tolerated dose (MTD), the highest dose given without causing unacceptable side effects, known as dose-limiting toxicities (DLTs).
Once a safe dose range is established, a main objective is evaluating the antibody’s anti-tumor activity. This involves measuring efficacy endpoints like the objective response rate (ORR), the proportion of patients whose tumors shrink by a certain amount, and the duration of response (DOR), which measures how long that shrinkage lasts. Researchers also assess disease control rate (DCR), a measure that includes patients whose tumors have shrunk or remained stable without growing.
Another objective is to understand the antibody’s behavior in the body, a field known as pharmacokinetics, which studies how the drug is absorbed, distributed, metabolized, and eliminated. Trials also assess immunogenicity, the potential for the patient’s body to develop its own antibodies against the therapeutic antibody, which could reduce its effectiveness.
Exploratory objectives in these trials often involve searching for biomarkers. Biomarkers are measurable substances in blood or tissue that can indicate a patient’s likely response to a treatment. For 4-1BB antibodies, researchers might look for 4-1BB expression on tumor-infiltrating immune cells or soluble 4-1BB levels in the blood. Identifying predictive biomarkers could allow doctors to select patients most likely to benefit from this immunotherapy.
Challenges with Systemic Toxicity
A significant hurdle in developing 4-1BB agonist antibodies has been managing systemic toxicity. Because these antibodies broadly stimulate the immune system, their effects are not confined to the tumor. This widespread activation can lead to off-target effects, where the heightened immune response causes inflammation and damages healthy tissues.
The most prominent side effect observed in early trials, particularly with the antibody urelumab, was liver toxicity, or hepatotoxicity. This occurs because the liver contains a large population of resident immune cells. When a potent 4-1BB agonist antibody is administered systemically, it can over-stimulate these liver-resident immune cells.
This over-activation triggers inflammatory events within the liver, leading to elevated liver enzymes, which are markers of liver damage. In severe cases, this can cause significant liver injury. Clinical trials of urelumab reported dose-dependent hepatotoxicity, including severe liver-related adverse events and two treatment-related deaths at higher doses. This forced a re-evaluation of the antibody’s dosage, with subsequent studies exploring lower doses that showed limited efficacy.
The experience with urelumab highlighted the balance between achieving an anti-tumor response and avoiding harmful toxicities. While antibodies like utomilumab had a better safety profile with no significant liver toxicity, they also showed modest anti-cancer activity on their own. This created a therapeutic dilemma: the antibodies potent enough to shrink tumors were often too toxic, and those that were safe were not effective enough as a monotherapy.
Advancements with Combination Approaches
To navigate toxicity and enhance anti-tumor effects, researchers are testing 4-1BB antibodies in combination with other cancer treatments. Combining therapies with complementary mechanisms may create a synergistic effect, producing a more powerful response than either agent alone. This approach could also allow for lower, safer doses of the 4-1BB agonist.
The most common combination is with immune checkpoint inhibitors, such as antibodies that block the PD-1 or PD-L1 pathways. Checkpoint inhibitors work by releasing a natural brake on the immune system. Using both therapies together is thought to provide a more robust activation of T-cells, helping to reinvigorate exhausted immune cells within the tumor and drive a stronger attack.
Preclinical studies showed that combining a 4-1BB agonist with a PD-1 antagonist leads to better tumor control compared to either therapy by itself. These results have led to clinical trials evaluating these combinations in patients with advanced cancers. Some next-generation therapies are bispecific antibodies, single molecules engineered to bind to two different targets simultaneously, like PD-L1 and 4-1BB, to deliver targeted stimulation.
Beyond checkpoint inhibitors, other combination strategies are being explored. These include pairing 4-1BB agonists with chemotherapy, radiation therapy, or other immunotherapies that target different co-stimulatory molecules to find optimal therapeutic partners.