Combined Therapy of PD-1 and LAG-3

Introduction to PD-1 and LAG-3

Programmed cell death-1 (PD-1), an immunoreceptor belonging to the CD28 family, negatively regulates antigen receptor signaling by interacting with either two ligands, PD-L1 or PD-L2. Therapies that target the PD-1 receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types.

Lymphocyte activation gene 3 (LAG-3) is a co-inhibitory receptor and may downregulate T cell responses via interaction with major histocompatibility complex class-II (MHC-II) on DCs. Thus, modulation of the LAG-3 pathway can impact autoimmunity and infections as well as cancer.

Double Blockade of PD-1 and LAG-3

Increasing evidence has elucidated that LAG-3 has remarkable cooperation with the quintessential inhibitory immune checkpoints PD-1/PD-L1, which can conjointly mediate immune homeostasis, abrogate autoimmune disease, and enhance tumor-induced tolerance. Indeed, LAG-3 and PD-1 are co-expressed on both CD4⁺ and CD8⁺ tumor-infiltrating lymphocytes (TILs) in several preclinical murine models of cancer, restricting autoimmunity and promoting tumor-induced tolerance. Nearly identical results are obtained in autoimmunity models, reinforcing the notion that LAG-3 and PD-1 are potentially synergistic in regulating T cell function.

In preclinical cancer models, co-blockade of the LAG-3 and PD-1 pathways has been shown to synergize to improve anti-tumor CD8⁺ T cell responses and cytokine production. Similarly, combined antibody-mediated blockade of LAG-3 and PD-1 results in tumor rejection in several models without any short-term evidence of autoimmune side effects. Overall, these valuable preclinical data suggest dual blockade of these receptors leads to decreased tumor growth and enhanced antitumor immunity-an effect that is more pronounced than a single blockade.

Fig.1 LAG-3. (Li, 2015)

Currently, a majority of clinical trials are ongoing to explore the therapeutic benefits of simultaneously targeting LAG-3 and PD-1 for various cancer entities focusing on solid tumors.

• The anti-LAG-3 antibody is in late-phase clinical trials in combination with the anti-PD-1 antibody for first-line advanced melanoma treatment. This regimen holds the promise of both efficacy and de-escalation of toxicity.
• LAG-3 inhibitor alone and in combination with PD-1 blockade is also in a clinical trial to assess the safety and tolerability as well as dose-limiting toxicity in subjects with advanced solid malignancies.

Although these drugs targeting LAG-3 are mainly used in clinical settings in combination with anti-PD-1 medication, some anti-LAG-3 drugs are generated to be bispecific and targeting both LAG-3 and PD-1. Therefore, the combined blockade of PD-1 and LAG-3 is a highly promising combinatorial strategy for the immune-based therapy of cancer.

Services at Creative Biolabs

Combining state-of-the-art technology with personal service and attention, Creative Biolabs offers a series of custom services for immune checkpoint PD-1 and LAG-3, including but not limited to:

• Immune Checkpoint Antibody Development
• Immune Checkpoint Targeted Small Molecule Drug Development
• Immune Checkpoint Assays
• Custom Immune Checkpoint Protein Development
• Immune Checkpoint Targeted Peptide Development
• Preclinical Research for Immune Checkpoint Drugs

Please do not hesitate to contact us for more detailed information.

Reference

1. Li, X.; et al. Emerging immune checkpoints for cancer therapy. Acta Oncologica. 2015, 54(10), pp.1706-1713.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.