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Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy.

ABSTRACT: Lymphocyte activation gene 3 (LAG-3) is expressed on activated T cells, natural killer cells or B cells, and functions to negatively regulate homeostasis of these cells. Anti-LAG-3 antibodies might be useful for antitumor immunotherapy. In this study, we characterized a novel anti-LAG-3 antibody, LBL-007, which was isolated from a human antibody phage display library. LBL-007 was found to specifically bind to human LAG-3 antigen, but not to human CD4 or mouse LAG-3. LBL-007 bound activated T cells and promoted interleukin-2 secretion. LBL-007 internalization efficacy by endocytosis into different cells was better than that of another anti-LAG-3 antibody, relatlimab analog. Moreover, LBL-007 was able to block LAG-3 binding to MHC class II molecules and liver sinusoidal endothelial cell lectin, and block LAG-3-induced downstream signaling. In mice transplanted with colorectal cancer cells, treatment with either anti-PD-1 antibody or LBL-007 (10 mg/kg per mouse twice a week for three weeks) resulted in a significant delay in tumor growth compared with control IgG treatment, and their combination was even more effective. Serum LBL-007 levels were highly stable in monkeys after a single intravenous injection of LBL-007 at 3, 10, or 30 mg/kg. This study demonstrated that the combination of LBL-007 with an anti-PD-1 antibody is a promising antitumor regimen for immunotherapy of solid tumors in future that deserves further study.

SUBMITTER: Yu X

PROVIDER: S-EPMC6748621 | biostudies-literature | 2019 Aug/Sep

REPOSITORIES: biostudies-literature

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Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy.

Yu Xiaojie X Huang Xiao X Chen Xiuxiu X Liu Jianfei J Wu Chenglin C Pu Qian Q Wang Yuxiao Y Kang Xiaoqiang X Zhou Lijun L

mAbs 20190626 6

Lymphocyte activation gene 3 (LAG-3) is expressed on activated T cells, natural killer cells or B cells, and functions to negatively regulate homeostasis of these cells. Anti-LAG-3 antibodies might be useful for antitumor immunotherapy. In this study, we characterized a novel anti-LAG-3 antibody, LBL-007, which was isolated from a human antibody phage display library. LBL-007 was found to specifically bind to human LAG-3 antigen, but not to human CD4 or mouse LAG-3. LBL-007 bound activated T cel ...[more]

PMID: 31242068

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Project description:BACKGROUND:Lymphocyte-activation gene (LAG)3 is a 498 aa transmembrane type I protein acting as an immune inhibitory receptor. It is expressed on activated lymphocytes, natural killer cells and plasmacytoid dendritic cells. In activated lymphocytes, LAG3 expression is involved in negative control of cell activation/proliferation to ensure modulation and control of immune responses. In view of its deregulated expression in tumor-infiltrating lymphocytes, LAG3, together with the additional immune checkpoint inhibitors CTLA4 and PD1, is considered a major target in order to reverse the immunosuppression typically mounting in oncologic diseases. Since many patients still fail to respond to current immune checkpoints-based therapies, the identification of new effective immune inhibitors is a priority in the ongoing fight against cancer. RESULTS:We identified a novel human single-chain variable fragment (scFv) Ab against a conformational epitope of LAG3 by in vitro phage display technology using the recombinant antigen as a bait. This scFv (referred to as F7) was characterized in terms of binding specificity to both recombinant antigen and human LAG3-expressing cells. It was then rebuilt into an IgG format pre-optimized for clinical usage, and the resulting bivalent construct was shown to preserve its ability to bind LAG3 on human cells. Next, we analyzed the activity of the anti-LAG3 scFvF7 using two different antigen-specific CD8+ T lymphocyte clones as target cells. We proved that the reconstituted anti-LAG3 F7 Ab efficiently binds the cell membrane of both cell clones after peptide-activation. Still more significantly, we observed a striking increase in the peptide-dependent cell activation upon Ab treatment as measured in terms of IFN-γ release by both ELISA and ELISPOT assays. CONCLUSIONS:Overall, the biotechnological strategy described herein represents a guiding development model for the search of novel useful immune checkpoint inhibitors. In addition, our functional data propose a novel candidate reagent for consideration as a cancer treatment.

Dataset Information

Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy.

Publications

Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy.

Similar Datasets

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