Over the last decade, antibodies that block extracellular receptors on our immune cells have redefined the treatment approach for certain cancers. Now, all eyes are on how using the opposite approach may help treat autoimmune and inflammatory diseases.
Our immune system is an intricate web of checks and balances meant to detect, identify, and destroy potential threats. Essential in this process are extracellular receptors, called checkpoint receptors, which serve as both markers and regulators of immune cell activation and function. They help regulate the immune systems’ response.
Research suggests that for people living with autoimmune and inflammatory diseases, such as atopic dermatitis or rheumatoid arthritis, their immune system is not able to damp down runaway cell proliferation.1
Targeting these checkpoints with an agonist antibody leverages the immune systems’ natural regulatory mechanisms to “hit the brakes” on runaway inflammation, so that their disease doesn’t continue its vicious cycle. Currently, there is a significant amount of ongoing clinical development to better understand how the power of checkpoint agonists can be leveraged therapeutically to restore immune balance. Importantly, checkpoint agonist therapeutics have been well tolerated in human trials to date.
Understanding the role of BTLA checkpoint receptors in regulating immune balance
One immune checkpoint receptor in particular, the B and T lymphocyte attenuator (BTLA), has emerged as a unique and interesting therapeutic target due to its essential role in modulating immune balance across a wide range of immune cells, including T cells, B cells, and dendritic cells.
BTLA interacts with its natural ligand, herpesvirus entry mediator (HVEM), to relay messages on the same or across different cells. This unique interaction between BTLA and HVEM creates a two-way communication network that relays signals to mount an immune response or damp it down.2
For example, in healthy cells when HVEM binds to BTLA, it gives the “hit the brakes” message to T cells so they do not raise an inappropriate immune response.3 However, in patients with atopic dermatitis and other autoimmune diseases, the communication line may be severed or garbled, altering BTLA or HVEM expression and activation.4 When this happens, they develop an exacerbated inflammatory response that, in many cases, is sustained through self-reinforcing cycles.
In the lab, data from models using mice demonstrate dysregulation of the BTLA pathway accelerates disease onset or exacerbates inflammatory disease, attacking the body’s own cells, tissues, and organs.5,6 When treated with a BTLA agonist, that T cell proliferation is inhibited, reducing the inflammatory cycle.
These promising early data in mice on the role of BTLA have prompted a number of clinical trials in humans studying if BTLA agonists can damp down immune cell activity and restore the body’s natural immune balance for different autoimmune and inflammatory diseases.
New clinical studies offer a chance for better patient outcomes
Atopic dermatitis, the most common inflammatory skin disease, is a systemic disease that causes dry, itchy, and inflamed skin which can impact people’s quality of life. People living with atopic dermatitis are also prone to asthma, hay fever, or food allergies, due to an overactive immune system. New research suggests that multiple different types of immune cells are involved in atopic dermatitis which are not broadly targeted by current therapies leading to suboptimal outcomes for patients, opening up the potential for new approaches to safely treat this extremely symptomatic skin condition.7
AnaptysBio is currently studying one such approach with a BTLA agonist monoclonal antibody, investigational ANB032, which has the potential to be a more potent or deeper immune cell modulator that can deliver durable responses and restore immune balance across a broader population of atopic dermatitis patients.
In a Phase 1 trial with healthy volunteers, ANB032 was generally well-tolerated, with no dose limiting toxicities and no discontinuations due to adverse events. Importantly, this study confirmed the pharmacodynamic activity of ANB032 in humans, with rapid and sustained engagement on B cells and T cells.8 ANB032 is now being studied in a global Phase 2b trial to further investigate its potential in atopic dermatitis.
As we continue to evolve our understanding of how to modulate our body’s immune system, the BTLA checkpoint receptor may prove to be a key to restoring immune balance and benefit people living with serious and debilitating autoimmune and inflammatory diseases. To find out more, visit us here.
- Parkin J, Cohen B. An overview of the immune system. Lancet. 2001;357(9270):1777-1789. doi:10.1016/S0140-6736(00)04904-7
- Murphy TL, Murphy KM. Slow down and survive: Enigmatic immunoregulation by BTLA and HVEM. Annu Rev Immunol. 2010;28:389-411. doi:10.1146/annurev-immunol-030409-101202
- Ning Z, Liu K, Xiong H. Roles of BTLA in Immunity and Immune Disorders. Front Immunol. 2021;12:654960. Published 2021 Mar 29. doi:10.3389/fimmu.2021.654960
- Wojciechowicz K, Spodzieja M, Lisowska KA, Wardowska A. The role of the BTLA-HVEM complex in the pathogenesis of autoimmune diseases. Cell Immunol. 2022;376:104532. doi:10.1016/j.cellimm.2022.104532
- Nakagomi D, Suzuki K, Hosokawa J, et al. Therapeutic potential of B and T lymphocyte attenuator expressed on CD8+ T cells for contact hypersensitivity. J Invest Dermatol. 2013;133(3):702-711. doi:10.1038/jid.2012.396
- Bekiaris V, Šedý JR, Macauley MG, Rhode-Kurnow A, Ware CF. The inhibitory receptor BTLA controls γδ T cell homeostasis and inflammatory responses. Immunity. 2013;39(6):1082-1094. doi:10.1016/j.immuni.2013.10.017
- Zheng C, Shi Y, Zou Y. T cell co-stimulatory and co-inhibitory pathways in atopic dermatitis. Front Immunol. 2023;14:1081999. Published 2023 Mar 13. doi:10.3389/fimmu.2023.1081999
- Khanskaya I, Pinkstaff J, Marino MH, Savall T, Li J, Londei M. A Phase 1 study of ANB019, an Anti-IL-36 Receptor Monoclonal Antibody, in Healthy Volunteers. https://www2.anaptysbio.com/wp-content/uploads/ANB019-Phase-1-Study-Poster-EAACI-2018.pdf Accessed May 18, 2023.