Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development

Gui, Xun; Deng, Mi; Song, Hao; Chen, Yuanzhi; Xie, Jingyuan; Z, Li; He, Li; Huang, Fangfang; Xu, Yadong; Anami, Yasuaki; Yu, Huixin; Yu, Chen; L, Li; Yuan, Zihao; Xu, Xiaoke; Wang, Q; Chai, Yan; Huang, Tao; Shi, Yunfan; Tsuchikama, Kyoji; Xc, Liao; Xia, Ningshao; Gf, Gao; Zhang, N; Zhang, CC; An, Zhisheng

doi:10.1158/2326-6066.cir-19-0036

Cited by 57 publications

(70 citation statements)

References 39 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The same cluster exhibits high expression of IL4I1, NFKBIA, VISTA , and LILRB4 . Like LILRB2, LILRB4-mediated ITIM signaling has a strong effect on the anti-inflammatory phenotype of myeloid cells ( 133 ), and we hypothesize that LILRB4 could act as a central regulator of the immunosuppressive cascade network in this myeloid cluster, as Deng et al ( 134 ) showed a significant decrease of NFKBIA (IκB) at the protein level, following genetic ablation of LILRB4 in myeloid cells ( 135 ). The additional correlation to VISTA within the same cluster is of particular importance, as VISTA is proving to be an attractive target to prevent inhibition of T-cell cytotoxicity ( 136 ).…”

Section: Tam/mdsc Identification Across Tumor Typesmentioning

confidence: 88%

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

View full text Add to dashboard Cite

Tumor-mediated regulation of the host immune system involves an intricate signaling network that results in the tumor's inherent survival benefit. Myeloid cells are central in orchestrating the mechanisms by which tumors escape immune detection and continue their proliferative programming. Myeloid cell activation has historically been classified using a dichotomous system of classical (M1-like) and alternative (M2-like) states, defining general pro- and anti-inflammatory functions, respectively. Explosions in bioinformatics analyses have rapidly expanded the definitions of myeloid cell pro- and anti-inflammatory states with different combinations of tissue- and disease-specific phenotypic and functional markers. These new definitions have allowed researchers to target specific subsets of disease-propagating myeloid cells in order to modify or arrest the natural progression of the associated disease, especially in the context of tumor-immune interactions. Here, we discuss the myeloid cell contribution to solid tumor initiation and maintenance, and strategies to reprogram their phenotypic and functional fate, thereby disabling the network that benefits tumor survival.

show abstract

Section: Tam/mdsc Identification Across Tumor Typesmentioning

confidence: 88%

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Antibody variable region genes were cloned from those positive B cells using methods described previously. 20 Expression and purification of mAbs Full length IgG was produced in human embryonic kidney Expi293F cells using an ExpiFectamine 293 Transfection Kit (Catalog #: A14528, Gibco) by cotransfection HEK293 cells with both heavy and light chain expression constructs. 20 After 7 days of fed-batch culture, the culture supernatants were harvested and antibodies were purified by affinity chromatography using protein A resin (Catalog #: 10-2001-XM, Repligen) as described previously.…”

Section: Generation Of Anti-lilrb1 Mabsmentioning

confidence: 99%

“…20 Expression and purification of mAbs Full length IgG was produced in human embryonic kidney Expi293F cells using an ExpiFectamine 293 Transfection Kit (Catalog #: A14528, Gibco) by cotransfection HEK293 cells with both heavy and light chain expression constructs. 20 After 7 days of fed-batch culture, the culture supernatants were harvested and antibodies were purified by affinity chromatography using protein A resin (Catalog #: 10-2001-XM, Repligen) as described previously. 20 Epitope binning and affinity measurement with bio-layer interferometry Classical sandwich epitope binning experiments were performed on an 8-channel Octet RED96 System as described.…”

Section: Generation Of Anti-lilrb1 Mabsmentioning

confidence: 99%

“…20 After 7 days of fed-batch culture, the culture supernatants were harvested and antibodies were purified by affinity chromatography using protein A resin (Catalog #: 10-2001-XM, Repligen) as described previously. 20 Epitope binning and affinity measurement with bio-layer interferometry Classical sandwich epitope binning experiments were performed on an 8-channel Octet RED96 System as described. 20 First, a baseline was established in kinetics buffer (Cat#18-1105, ForteBio) for 3 min.…”

Section: Generation Of Anti-lilrb1 Mabsmentioning

confidence: 99%

“…20 Epitope binning and affinity measurement with bio-layer interferometry Classical sandwich epitope binning experiments were performed on an 8-channel Octet RED96 System as described. 20 First, a baseline was established in kinetics buffer (Cat#18-1105, ForteBio) for 3 min. Then antibodies (30 µg/mL) were captured by protein A biosensors (Cat#18-5010, ForteBio) for 4 min.…”

Section: Generation Of Anti-lilrb1 Mabsmentioning

confidence: 99%

See 2 more Smart Citations

Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells

Chen

Deng

et al. 2020

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundCurrent immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment.MethodsFirst, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice.ResultsWe demonstrate that percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+ NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo.ConclusionsOur results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.

show abstract

Leukocyte immunoglobulin‐like receptor B1 and B4 (LILRB1 and LILRB4): Highly sensitive and specific markers of acute myeloid leukemia with monocytic differentiation

Churchill

Fuda

et al. 2020

Cytometry Part B Clinical

Self Cite

View full text Add to dashboard Cite

Background: Acute myeloid leukemia (AML) with monocytic differentiation (M-AML) remains a diagnostic challenge largely due to lack of sensitive and specific markers for immature monocytes. The immunoglobulin-like inhibitory receptors, LILRB1 and LILRB4, are expressed on monocytes but have not yet been systematically evaluated in the clinical setting. Methods: We evaluated the diagnostic performance of LILRB1 and LILRB4 as monocytic markers for both immature and mature monocytes in comparison to other myelomonocytic markers including CD14, CD15, CD33, CD36, and CD64 in eight cases of control bone marrow (BM, 5) and peripheral blood (PB, 3), 64 cases of (M-AML), and 57 cases of AML without monocytic differentiation (NM-AML) by flow cytometric immunophenotyping.Results: In control BM, LILRB1 and LILRB4 were consistently expressed on monocytes at all stages of maturation, from CD34 + /CD14 − monocytic precursors to CD14 −/dim+ maturing and CD14 + mature monocytes. In M-AML, LILRB1 and LILRB4 were consistently expressed on monocytes, regardless of the degree of maturity, from CD14 −/dim+ monoblasts/promonocytes to CD14 + mature monocytes but were not expressed on myeloblasts.The diagnostic performances as a monocytic marker assessed by sensitivity/specificity were 100%/100% for LILRB1/LILRB4, 100%/82% for CD11b, 80%/100% for CD14, 100%/81% for CD64, 100%/58% for CD15/CD33, and 89%/97% for CD36/CD64. Conclusion:The co-expression of LILRB1/LILRB4 outperformed other myelomonocytic markers as a highly sensitive and specific marker for monocytes at all stages of maturation and could reliably distinguish M-AML from NM-AML. LILRB4 additionally represents a novel therapeutic target for treating M-AML.

show abstract

Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development

Cited by 57 publications

References 39 publications

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells

Leukocyte immunoglobulin‐like receptor B1 and B4 (LILRB1 and LILRB4): Highly sensitive and specific markers of acute myeloid leukemia with monocytic differentiation

Contact Info

Product

Resources

About