Immune checkpoint inhibitors, which target coinhibitory T cell molecules to promote anticancer immune responses, are now regarded as a novel cancer therapy of enormous potential. Nowadays, defining new targets and combination of immune checkpoint inhibitors have been urgently needed. And several studies have provided evidence that the combination of two immunotherapies can enhance efficacy. Creative Biolabs, who always focuses on the hot point of antibody-based drug discovery, has successfully established an efficient Magic™ “humanized” animal platform, and is able to provide humanized PD-1/BTLA dual immune checkpoint knock-in mice for our clients all over the world.

PD-1 and BTLA Signaling Pathway

Checkpoint programmed death-1 (PD-1)/programmed cell death ligands (PD-Ls) have been identified as negative immunoregulatory molecules that promote immune evasion of tumor cells. Anti-PD1 therapies show a significant improvement in response to many standards of care regimens, but there is a significant need to further increase cancer patient responses. Recently, several clinical studies have shown improved response rate when combining anti-PD1 and anti-BTLA therapies. B- and T-cell lymphocyte attenuator (BTLA), also been designated as CD272, is an immunoglobulin-like protein. BTLA belongs to CD28 family and is structurally similar to cytotoxic T lymphocyte activation antigen (CTLA)-4 and programmed death (PD)-1. BTLA is an inhibitory co-receptor which modulates T cell function and is a marker of “exhausted” T cells. The inhibitory signal mediated by BTLA is initiated following engagement with herpesvirus entry mediator (HVEM), a ubiquitous receptor that is highly expressed on malignant cells.

Combination of Anti-PD-1 and Anti-BTLA Immunotherapies

Not only playing an important role in tumor immunotherapy, PD-1 antibodies enhance cytokine production and CD8 T cell proliferation in response to HIV-antigens. BTLA or TIM-3 antibodies also enhance proliferation of CD8 T cells and the use of these antibodies in combination with PD-1 blockade is significantly effective in augmenting cytokine production and CD8 T cell proliferation than PD-1 antibodies alone.

In addition, PD-1 has been involved in peripheral tolerance, and the coinhibitory receptor BTLA has been implicated in the regulation of autoimmune and may potentially play an important role in alloimmune responses. A study focused on cardiac allografts shows that combination of anti-BTLA mAb (6B2) and anti-PD-1 mAb (PIM-2) could induce hyporesponsiveness of fully MHC-mismatched cardiac allografts.

Magic™ Humanized PD-1/BTLA Dual Immune Checkpoint Knock-In Mice Fig.1. Known signaling pathways of selected checkpoint molecules and current therapeutics. (Nirschl & Drake, 2013)

Development of Humanized PD-1/BTLA-4 Dual Immune Checkpoint Knock-In Mice

More recently, it has been reported that BTLA antagonist monoclonal antibody enhances the effect of anti-PD1 therapy in preclinical mouse tumor models. This provides “proof of concept” that the combination of two immunotherapies can enhance efficacy. Consequently, dual blockade of PD-1 and BTLA with bispecific antibodies has drawn great attention in research and development of combination immunotherapy drugs. As a world leader in this field, Creative Biolabs has already launched an array of well-established Magic™ “humanized” animal models, including the humanized PD-1/BTLA dual immune checkpoint knock-in mice. Please feel free to contact us for more detailed information.

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


  1. Nirschl, C. J.; Drake, C. G. Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy. Clinical Cancer Research an Official Journal of the American Association for Cancer Research. 2013, 19(18):4917.

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