Tumor Necrosis Factor Receptor Superfamily Member 10B (TNFRSF10B), also known as Death Receptor 5 (DR5), is a key molecule mediating the extrinsic apoptotic pathway. Its characteristic of being generally highly expressed in tumor cells while lowly expressed in normal tissues makes it an ideal target for tumor-targeted therapy. This article systematically elaborates on the biological properties of TNFRSF10B, the evolution of targeted therapy strategies, the innovative application of bispecific antibodies, and the current challenges, providing a reference for in-depth research in this field.
TNFRSF10B belongs to the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) and is located on chromosome 8p21-22. The protein encoded by it consists of 440 amino acids, including an extracellular ligand-binding domain, a transmembrane domain, and an intracellular death domain (DD). The extracellular domain can specifically bind to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and the intracellular death domain recruits adaptor proteins (such as FADD) and initiator caspases (procaspase-8/10) to form a death-inducing signaling complex (DISC), initiating the caspase cascade reaction and ultimately leading to cell apoptosis. This ligand-dependent activation mode makes TNFRSF10B a "molecular switch" of the extrinsic apoptotic pathway.
Clinical studies have shown that TNFRSF10B is highly expressed in various solid tumors (such as colorectal cancer, non-small cell lung cancer, breast cancer) and hematological malignancies (such as multiple myeloma, lymphoma), and its expression level is positively correlated with tumor malignancy and poor prognosis. For example, in colorectal cancer patients, the positive expression rate of TNFRSF10B can reach 60%-80%, which is significantly higher than that in normal intestinal mucosal tissue (<10%). The molecular mechanism of this tumor-specific expression pattern has not been fully elucidated. It is currently believed that it may be related to the activation of tumor-related transcription factors such as hypoxia-inducible factor (HIF-1α) and p53. These factors can directly bind to the TNFRSF10B promoter region to promote its transcription.
The tumor-specific expression pattern of TNFRSF10B makes it an ideal therapeutic target: by selectively activating TNFRSF10B on the surface of tumor cells, it can induce tumor apoptosis while avoiding damage to normal tissues, which lays the foundation for precise tumor therapy.
The discovery of TRAIL, the natural ligand of TNFRSF10B, provided the first tool for targeted therapy. Recombinant soluble TRAIL (such as Apo2L/TRAIL) can efficiently induce apoptosis in various tumor cells in vitro with low toxicity to normal cells. However, clinical translation faces significant challenges: first, the half-life is extremely short (only a few minutes), requiring frequent administration to maintain effective concentrations; second, natural TRAIL has limited aggregation ability, which can only induce the formation of a small number of TNFRSF10B trimers, making it difficult to trigger a strong apoptotic signal. Although subsequent derivatives such as circularly permuted TRAIL (CPT, such as aponermin) were developed, which extended the half-life to about 1 hour through structural optimization, the clinical response rate of monotherapy is still less than 20%, and it needs to be used in combination with chemotherapy drugs to show efficacy.
In view of the shortcomings of TRAIL derivatives, research has turned to agonistic monoclonal antibodies targeting TNFRSF10B. Such antibodies (such as lexatumumab, conatumumab) can theoretically stably activate TNFRSF10B by simulating the binding mode of TRAIL. However, clinical studies have shown that their monotherapy efficacy is limited: in solid tumor clinical trials, the objective response rate (ORR) is generally less than 10%. Mechanistic studies have revealed that IgG-type monoclonal antibodies are bivalent molecules that can only bind to 2 TNFRSF10B molecules and cannot form effective aggregates; their activity is highly dependent on the binding of the Fc segment to FcγRII on the surface of B cells, enhancing receptor clustering through "secondary cross-linking". However, in the human tumor microenvironment, B cell infiltration is scarce and the high concentration of endogenous IgG in serum will competitively bind to FcγRII, resulting in a significant reduction in cross-linking efficiency and ultimately limiting efficacy.
To solve the problem of insufficient TNFRSF10B aggregation, Bispecific Apoptosis Triggers (BAT) came into being. BAT targets tumor-associated antigens (TAA, such as FOLR1, CDH17) through one antigen-binding arm and specifically binds to TNFRSF10B through the other arm, achieving "tumor-selective aggregation" of TNFRSF10B by virtue of the high expression characteristics of TAA on the surface of tumor cells. For example, BAT targeting FOLR1 and TNFRSF10B can form high-density antibody clusters on the surface of tumor cells through multivalent binding of FOLR1, thereby promoting the supramolecular aggregation of TNFRSF10B and strongly activating apoptotic signals. This design not only avoids dependence on FcγRII but also can induce apoptosis of adjacent TAA-negative tumor cells through "trans-crosslinking" (bystander effect), effectively addressing the problem of tumor heterogeneity.
Compared with traditional therapeutic strategies, bispecific antibodies targeting TNFRSF10B have significant advantages:
Mechanistic uniqueness: They act by directly activating the extrinsic apoptotic pathway, which is different from ADCs that rely on cytotoxic payloads or BiTE therapies that rely on immune cells, avoiding the risks of chemotherapy-acquired resistance and cytokine release syndrome.
Tumor selectivity: With the targeting of TAA, they only induce TNFRSF10B aggregation on the surface of tumor cells, reducing the probability of misactivation of cells with low TNFRSF10B expression in normal tissues (such as liver and intestine).
Manufacturing convenience: They adopt standard IgG antibody production processes without the complex and expensive chemical conjugation steps required for ADCs, resulting in lower production costs and higher batch-to-batch consistency.
Bystander effect: Similar to ADCs with cleavable linkers and different from monospecific anti-DR5 drugs, BATs exhibit bystander cytotoxic activity. They can kill tumor cells through trans-clustering of TNFRSF10B on adjacent cells, potentially enhancing their anti-tumor activity and being able to eradicate tumors with heterogeneous TAA expression.
Despite the broad prospects, bispecific antibodies targeting TNFRSF10B still have problems to be solved:
Receptor aggregation efficiency: The expression levels and spatial distribution of different TAAs vary greatly. For example, the extracellular repeat sequences of CDH17 have low homology, resulting in some BATs only being able to achieve limited cross-linking. It is necessary to optimize the affinity and spatial configuration of the antigen-binding arm through antibody engineering.
Normal tissue toxicity: Some multivalent antibodies (such as HexaBody-DR5/DR5) cause hepatotoxicity due to overactivation of a small amount of TNFRSF10B in normal tissues, suggesting that it is necessary to balance the intensity of receptor aggregation and safety.
Drug resistance mechanisms: Tumor cells can develop resistance by down-regulating TNFRSF10B expression, mutating the death domain, or activating anti-apoptotic pathways (such as NF-κB). It is necessary to combine other targets (such as BCL-2 family members) to reverse resistance.
As a key molecule in the extrinsic apoptotic pathway, the tumor-specific expression of TNFRSF10B provides a unique target for precise therapy. From early TRAIL derivatives to monoclonal antibodies, and then to bispecific antibodies (BAT), the evolution of targeting strategies has always centered on the core issue of "how to efficiently and safely activate TNFRSF10B". The tumor-selective aggregation achieved by BAT through bispecific design represents the most promising solution currently, but it still needs to make breakthroughs in receptor cross-linking efficiency, toxicity control, and drug resistance management.
Future research can proceed from three aspects: first, the complex structure of TNFRSF10B and BAT through cryo-electron microscopy to guide the rational design of antibodies; second, develop bifunctional antibodies targeting TNFRSF10B and immune checkpoints (such as PD-L1) to synergistically activate apoptosis and immune responses; third, conduct precise stratification based on patients' TNFRSF10B expression and TAA profiles to achieve individualized therapy. With the advancement of technology, therapeutic strategies targeting TNFRSF10B are expected to provide a new breakthrough for tumor therapy.
Business license (three certificates in one) 