Immune checkpoint inhibitors that target coinhibitory T cell molecules are becoming a new pillar of cancer therapy by promoting anticancer immune responses. Nevertheless, current immune checkpoint-based therapies are effective only for a portion of cancer patients and are facing additional challenges due to the acquired resistance. Combining immunotherapeutic antibodies for the treatment of cancer patients have exhibited significant benefits over single-agent treatment. As always being a leading innovator, scientists in Creative Biolabs spare no effort to develop the Magic™ dual immune checkpoint “humanized” mouse models for your study of novel antibody drug discovery, with extensive experience and excellent technology. Especially, we now provide the humanized PD-L1/LAG-3 dual immune checkpoint knock-in mice for our clients all over the world.

PD-L1 and LAG-3 Immune Checkpoint Pathway

PD-L1 (Programmed death-ligand 1) is a ligand of PD-1 and represent a crucial step in immune checkpoint control system regulating peripheral T cell responses that enable self-tolerance and prevent auto-immune reactions. As expressed in the tumor microenvironment, PD-L1 causes T cell suppression through PD-1 ligation, leading to tumor escape from immune surveillance and therefore resistance.

LAG-3 (lymphocyte-activation gene 3), also named as CD223 (cluster of differentiation 223), is an immune checkpoint receptor expressed on the cell surface of effector T cells and regulatory T cells (Tregs), and functions as a co-inhibitory molecule to control T cell response, activation, and growth. The major of LAG-3 is class II MHC, which plays a vital role in presenting antigen for recognition by T cells. LAG-3 negatively regulates T-cell proliferation and development of lasting memory T cells.

Magic™ Humanized PD-L1/LAG-3 Dual Immune Checkpoint Knock-In MiceFig.1. Schematic representation of immune co-stimulatory and co-inhibitory molecule receptors on T-cells and their ligands among T cells, antigen-presenting cells and tumor cells, and targeting strategies and agents of immune checkpoint blockade therapy. (Liu and Cho, 2017)

Combination of Anti-PD-L1 and Anti-LAG-3 Immunotherapies

As a potentially synergistic immune pathway to PD-1/PD-L1, LAG-3 has been regarded as an immune checkpoint receptor that modulates T cell function and whose inhibition may significantly increase antitumor effect. A recent study suggests that an alternative to combining two antibodies is the discovery of bispecific antibodies that may lead to new mechanisms of action that are unable to attain by combinations. The anti-LAG-3/PD-L1 mAb², a bispecific antibody which is engineered to bind murine LAG-3 and PD-L1 simultaneously and with nanomolar affinities, shows an increase of antitumor activity in the CT26 murine colon cancer model, as compared to the antibodies given in combination. The outcome of this preclinical study proves the necessity of developing an anti-human LAG-3/PD-L1 mAb² for the treatment of cancer patients.

Development of Humanized PD-L1/LAG-3 Dual Immune Checkpoint Knock-In Mice

Antibodies (Abs) against programmed cell death protein-ligand 1 (PD-L1) have generated positive clinical responses and an increased survival in many types of cancer patients. However, a single agent like anti-PD-1/PD-L1 Ab seems to be unable to improve clinical outcomes in most patients. Thus, to develop combination immunotherapy strategies is a potential way to solve this problem. Creative Biolabs, who always focuses on the study spotlight, has already established an array of validated dual “humanized” immune checkpoint knock-in mouse models by our advanced transgenic technology. Now, we are proud to provide the PD-L1/LAG-3 dual immune checkpoint knock-in mouse as a product, and we also provide various laboratory evaluation of assays for your drug discovery studies. Our Magic™ dual immune checkpoint “humanized” mouse models are ideal tools for evaluation studies on the combination therapies and bispecific antibody, with reliable validation data. Please feel free to contact us for more information.

Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:

Reference

  1. Liu, X. and Cho, W.C., Precision medicine in immune checkpoint blockade therapy for non-small cell lung cancer. Clinical and translational medicine. 2017, 6(1), p.7.

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