Harnessing 4-1BB Immunomodulation for Cancer Therapy

Harnessing 4-1BB Immunomodulation for Cancer Therapy

Introduction


The tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as 4-1BB or CD137, has emerged as a promising target for cancer immunotherapy. This costimulatory receptor, primarily expressed on activated T cells and natural killer (NK) cells, plays a crucial role in enhancing anti-tumor immune responses. In recent years, the development of agonistic antibodies targeting 4-1BB has gained significant attention in the field of cancer research and clinical oncology.

 

Mechanism of Action


4-1BB signaling promotes T cell proliferation, survival, and effector function through the activation of NF-κB, PI3K, and MAPK pathways. Upon engagement with its ligand (4-1BBL) or agonistic antibodies, 4-1BB triggers the recruitment of TNFR-associated factors (TRAFs), leading to enhanced cytokine production, particularly IFN-γ and IL-2. This activation not only augments the cytotoxic activity of CD8+ T cells but also mitigates activation-induced cell death, thereby sustaining the anti-tumor immune response.

 

Anti-4-1BB Antibodies in Cancer Research and Therapy


Several anti-4-1BB antibodies have been developed and tested in preclinical and clinical settings:

  1. Urelumab (BMS-663513): This fully human IgG4 monoclonal antibody was one of the first 4-1BB agonists to enter clinical trials. In preclinical studies, urelumab demonstrated significant anti-tumor activity in various cancer models, including melanoma and lymphoma. However, clinical development was temporarily halted due to hepatotoxicity concerns in phase II trials. Subsequent studies have explored lower dosing regimens to mitigate these adverse effects while maintaining efficacy.
  2. Utomilumab (PF-05082566): Developed by Pfizer, this fully human IgG2 monoclonal antibody has shown a more favorable safety profile compared to urelumab. Preclinical studies demonstrated enhanced T cell proliferation and anti-tumor activity in multiple myeloma and lymphoma models. Phase I trials have reported encouraging results in combination with pembrolizumab for solid tumors and lymphoma.
  3. ADG106: This novel anti-4-1BB agonist, developed by Adagene, utilizes a dynamic precision masking technology to enhance tumor-specific activation. Preclinical studies have shown potent anti-tumor effects with a reduced risk of systemic toxicity. Early-phase clinical trials are currently evaluating its safety and efficacy in advanced solid tumors and lymphomas.
  4. LVGN6051: Developed by Lyvgen Biopharma, this bispecific antibody targets both 4-1BB and PD-L1. Preclinical data have demonstrated superior tumor growth inhibition compared to monotherapy approaches. Phase I trials are ongoing to assess its potential in treating advanced solid tumors.

 

Preclinical Anti-4-1BB Antibodies


While human antibodies are crucial for clinical development, preclinical research utilizing anti-mouse and anti-rat 4-1BB antibodies has been instrumental in elucidating the mechanism and potential of 4-1BB immunomodulation. These studies have paved the way for clinical translations and continue to provide valuable insights into combination strategies and novel approaches.

  1. 3H3: This rat anti-mouse 4-1BB monoclonal antibody has been widely used in preclinical studies. Melero et al. (1997) demonstrated that 3H3 could eradicate established tumors in mice, marking a significant milestone in 4-1BB cancer immunotherapy research. Subsequent studies have used 3H3 to investigate combination therapies, mechanisms of action, and potential adverse effects.
  2. LOB12.3: Another rat anti-mouse 4-1BB antibody, LOB12.3 has been employed in various preclinical models. Narazaki et al. (2010) used this antibody to demonstrate the synergistic effects of combining 4-1BB activation with adoptive T cell therapy in a murine model of melanoma.
  3. 2A: This mouse anti-rat 4-1BB monoclonal antibody has been valuable in studying 4-1BB signaling in rat models. Myers et al. (2006) utilized 2A to investigate the role of 4-1BB in graft-versus-host disease, providing insights that are relevant to both transplantation medicine and cancer immunotherapy.
  4. 20H4.9: Developed by Bristol-Myers Squibb, this hamster anti-mouse 4-1BB antibody has been used in preclinical studies to evaluate combination therapies. For instance, Youlin et al. (2013) employed 20H4.9 in combination with IL-12 gene therapy to enhance anti-tumor immunity in a murine hepatocellular carcinoma model.

These preclinical antibodies have been crucial in:

  • Establishing proof-of-concept for 4-1BB-targeted cancer immunotherapy
  • Investigating potential combination strategies with other immunomodulatory agents, chemotherapies, and targeted therapies
  • Elucidating mechanisms of action and potential adverse effects
  • Optimizing dosing schedules and administration routes
  • Identifying biomarkers of response and resistance


The insights gained from these preclinical studies have been instrumental in guiding the development of human anti-4-1BB antibodies and informing clinical trial designs. As research continues, these tools remain valuable for exploring novel combination approaches and understanding the complexities of 4-1BB signaling in the tumor microenvironment.

Combination Strategies


The potential of 4-1BB agonists in combination with other immunotherapies has garnered significant interest. Preclinical studies have shown synergistic effects when combining 4-1BB activation with checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies. This approach aims to simultaneously remove immunosuppressive signals while enhancing T cell activation, potentially overcoming resistance mechanisms observed in monotherapy regimens.

Additionally, combining 4-1BB agonists with conventional therapies, such as radiation or chemotherapy, has shown promise in preclinical models. These combinations may enhance immunogenic cell death and promote a more favorable tumor microenvironment for immune cell infiltration and activation.

Challenges and Future Directions


Despite the promising results observed with 4-1BB agonists, several challenges remain. The hepatotoxicity associated with some agents, particularly at higher doses, highlights the need for careful dosing strategies and the development of more tumor-specific approaches. Ongoing research focuses on optimizing antibody design, exploring novel delivery methods, and identifying predictive biomarkers to enhance efficacy while minimizing systemic toxicity.

Furthermore, elucidating the complex interplay between 4-1BB signaling and other immunomodulatory pathways will be crucial for designing rational combination therapies. As our understanding of the tumor immune microenvironment evolves, so too will our ability to harness the full potential of 4-1BB immunomodulation for cancer therapy.

In conclusion, the targeting of 4-1BB represents a promising avenue for enhancing anti-tumor immunity. From foundational preclinical studies using mouse and rat models to ongoing clinical trials with human antibodies, 4-1BB immunomodulation continues to demonstrate significant potential. As ongoing research continues to refine our approach to 4-1BB agonism, it is likely that this immunomodulatory strategy will play an increasingly important role in the future landscape of cancer immunotherapy.

 

ichorbio supplies the following anti-4-1BB antibodies:

Anti-Mouse 4-1BB (3H3) In Vivo Antibody - Low Endotoxin

Urelumab Biosimilar - Research Grade

Utomilumab Biosimilar - Research Grade