Combined Therapy of CTLA-4 and LAG-3

Introduction to CTLA-4 and LAG-3

Lymphocyte activation gene-3 (LAG-3, CD223) is another surface molecule of the immunoglobulin superfamily that plays an important role in the negative regulation of T cell proliferation via binding to MHC class II with high affinity. LAG-3 regulates anti-tumor immune responses in a pattern similar to CTLA-4, a well-known cancer immune checkpoint. The existing intersections of their signal transduction pathways may lead to the intriguing functional similarity of LAG-3 and CTLA-4. Both CTLA-4 and LAG-3 can inhibit the TCR signaling pathway, arrest cell cycle progression, negatively modulate T cell homeostasis, trigger the immunosuppressive function of Tregs, and exert essential effects on DCs.

Double Immune Checkpoint Blockade of CTLA-4 and LAG-3

The application of LAG-3 does play an important role in anti-tumor responses and maybe better when combing with anti-CTLA-4 and anti-PD-1/L1 antibodies. In acute graft-versus-host disease (GVHD), both human and murine experimental evidence demonstrates that co-blockade using tetravalent CTLA-4-Ig and LAG-3-Ig could synergistically suppress T cell responses, prevent acute GVHD, and decrease GVHD fatality rates as well. A recent study, which assesses the therapeutic effects of the CTLA-4 antibodies might increase frequencies of tumor-infiltrating T cells expressing LAG-3 in metastatic melanoma patients. It is also notable that a new phase I/II clinical trial has recently been opened to investigate the efficacy of triple targeting LAG-3, PD-1, and CTLA-4, which may be a novel combinatorial strategy in cancer treatment autoimmune disorders.

Another study has observed increased expression of TIM-3, LAG-3, CTLA-4, and 2B4 on CD8 and CD4 T cells in myeloma-bearing mice. Anti-myeloma synergy occurs when the PD-1/PD-L1 axis is blocked in combination with blocking TIM-3, LAG-3, or CTLA-4. Interestingly, blockade of LAG-3, TIM-3, or CTLA-4 alone has only modest or no effect on eliminating myeloma. The blocking of these constitutive inhibitory signals may have an observable anti-tumor effect only when dominant inhibitory signaling through PD-1 is blocked. In contrast, when combined with PD-L1 blockade, potent anti-myeloma effects are observed when each of these pathways is targeted. The results show that LAG-3 blockade in combination with PD-1 and CTLA-4 blockade synergistically may improve anti-tumor responses.

Fig.1 LAG-3 structure and ligands. (Ruffo, 2019)

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 CTLA-4 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. Ruffo, E.; et al. Lymphocyte-activation gene 3 (LAG3): the next immune checkpoint receptor. Seminars in immunology. 2019, Vol. 42.

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