4-1BB (CD137, TNFRSF9) is a crucial co-stimulatory receptor on T cells, discovered in 1989. In 1997, scientists at BMS published in Nature Medicine, demonstrating that the 4-1BB monoclonal antibody could induce improved activation of anti-tumor T cells, leading to the eradication of tumors in mouse models. Subsequently, BMS developed the 4-1BB agonistic antibody urelumab, but it exhibited significant hepatotoxicity.
First-Generation 4-1BB Agonists
The first generation of 4-1BB agonists is represented by urelumab (BMS-663513) and utomilumab (PF-05082566). Clinical development of 4-1BB antibody agonists began in 2005 with urelumab for the treatment of advanced cancer (NCT00309023). Initial results were promising, but two fatal adverse events related to liver toxicity occurred. Subsequent attempts with a safe dose (0.1 mg/kg) showed limited efficacy.
The second 4-1BB agonistic antibody, utomilumab (PF-05082566), entered clinical trials in 2011 (NCT01307267). Unlike urelumab, utomilumab did not induce significant toxicity but demonstrated very limited efficacy, even when combined with ipilimumab, leading to its eventual discontinuation.
Two Paths of Second-Generation 4-1BB Agonists
The primary challenge lies in understanding the positioning of 4-1BB: whether it functions as a co-stimulatory molecule (immune modulator) or plays an auxiliary role.
Using 4-1BB agonists as monotherapy at safe doses is insufficient to fully activate T cells. Increasing the dosage poses the risk of hepatotoxicity.
The two paths for second-generation 4-1BB agonists involve either combining them with potent drugs or developing bispecific/multispecific antibodies.
- Combination Therapy
While 4-1BB expression correlates positively with the functionality of anti-tumor CD8+ TILs in solid tumors, 4-1BB expression on T cells is diverse and dynamic. To fully exploit the effects of 4-1BB agonists, combination therapies that enhance 4-1BB expression are considered ideal.
Combining with immune checkpoint inhibitors (most commonly used) has shown synergistic effects in preclinical studies. In clinical trials, 12 different 4-1BB agonists have been combined with PD-(L)1 inhibitors, optimizing the mechanism of action through receptor occupancy.
Apart from immune checkpoint inhibitors, Roche’s RO7227166 (CD19X4-1BB) is being studied in combination with Cibisatamab (CEAXCD3) or anti-CD20 monoclonal antibody Obinutuzumab (Gazyva) for treating B-cell non-Hodgkin lymphoma. Legend Biotech’s LVGN6051 is combined with VEGFR inhibitor Anlotinib.
Bispecific/Trispecific/Four-Specific 4-1BB Agonists
Another group of second-generation 4-1BB agonists involves bispecific, trispecific, or four-specific antibodies. One arm of the antibody targets 4-1BB, and the second target varies, including tumor cell surface molecules (HER2, PSMA, EGFRvIII, Claudin18.2, ROR1, Nectin-4, CD47, CD19, etc.), tumor stroma and tumor-infiltrating lymph node surface molecules (such as FAP), tumor cells, and antigen-presenting cell surface molecules (such as PD-L1), or molecules expressed exclusively on immune cells (CD40, OX40, CD3).
4-1BB ranks as the 6th target for bispecific antibodies and holds the 1st position for non-T cell engaging bispecifics, partnering with PD-L1.
Conclusion
Over the past five years, research on second-generation 4-1BB agonists has significantly expanded, overcoming the limitations of the first generation to achieve safe and effective 4-1BB aggregation. So far, all 4-1BB agonists have demonstrated good safety and tolerability with controllable irAEs. However, effectiveness still awaits further validation over time.
Ongoing clinical trials for 4-1BB agonists
| NCT# | Study Title |
| NCT05159388 | A Study of PRS-344/S095012 (PD-L1x4-1BB Bispecific Antibody-Anticalin Fusion) in Patients With Solid Tumors |
| NCT05117242 | Safety and Efficacy Study of GEN1046 as a Single Agent or in Combination With Pembrolizumab for Treatment of Recurrent (Non-small Cell) Lung Cancer |
| NCT04144842 | Phase 1 Study in Patients With Advanced Solid Malignancies to Evaluate the Safety of ATOR-1017 |
| NCT03364348 | 4-1BB Agonist Monoclonal Antibody PF-05082566 With Trastuzumab Emtansine or Trastuzumab in Treating Patients With Advanced HER2-Positive Breast Cancer |
| NCT04826003 | Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290 In Combination With Cibisatamab With Obinutuzumab Pre-Treatment |
| NCT05523947 | Clinical Trial of YH32367 in Patients With HER2 Positive Locally Advanced or Metastatic Solid Tumor |
| NCT05564806 | Study of YH004 (4-1BB Agonist Antibody) in Advanced Solid Tumors And Relapsed Or Refractory Non-Hodgkin Lymphoma |
| NCT03330561 | PRS-343 in HER2-Positive Solid Tumors |
| NCT05301764 | A Study of LVGN6051 Combined With Anlotinib in Patient With Soft Tissue Sarcoma |
| NCT04740424 | FS222 First in Human Study in Patients With Advanced Malignancies |
| NCT04121676 | Anti-CD137 and Anti-CTLA-4 Monoclonal Antibody in Patients With Advanced Cancer |
| NCT05360381 | HLX35(EGFR/4-1BB Bispecific) in Patients With Advanced or Metastatic Solid Tumors |
| NCT04648202 | FS120 First in Human Study in Patients With Advanced Malignancies |
| NCT05614258 | Study of ADG206 in Subjects With Advanced/Metastatic Solid Tumors |
| NCT04077723 | A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of RO7227166 in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-Treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin’s Lymphoma |
| NCT05040932 | Study of YH004 (4-1BB Agonist Antibody) in Advanced or Metastatic Malignancy |
| NCT04762641 | This is a Study to Evaluate the Safety and Tolerability of ABL503, and to Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of ABL503 in Subjects With Any Progressive Locally Advanced or Metastatic Solid Tumors |
| NCT03809624 | Study of INBRX-105 and INBRX-105 With Pembrolizumab in Patients With Solid Tumors Including Head and Neck Cancer |