LILRB1

Detailed Information

Leukocyte Immunoglobulin-like Receptor Subfamily B Member 1 (LILRB1), also known as ILT2, is a member of the leukocyte immunoglobulin-like receptor (LIR) family and plays a crucial inhibitory role in immune regulation. Structurally, LILRB1 contains four extracellular immunoglobulin (Ig)-like domains, a transmembrane domain, and four intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs). These structural features enable it to transmit inhibitory signals upon ligand binding, thus regulating various immune responses.

Among the LILRB family members, LILRB1 has the broadest expression profile. It is expressed not only on innate immune cells like natural killer (NK) cells, monocytes/macrophages, eosinophils, basophils, and dendritic cells, but also on adaptive immune cells such as B cells and multiple T cell subsets. Furthermore, LILRB1 is found on decidual macrophages during pregnancy and osteoclasts involved in bone resorption, indicating its wide-ranging physiological roles.

Figure 1. Structure of LILRB1 and immune inhibitory functions. (Zeller T, et al., 2023)

Functional Role of LILRB1

LILRB1 acts as an immune checkpoint receptor, transmitting inhibitory signals that suppress cellular immune functions. Upon binding to ligands—most notably HLA class I molecules, including the non-classical MHC molecule HLA-G—LILRB1 becomes phosphorylated at its ITIM motifs. These phosphorylated tyrosines then recruit phosphatases such as SHP-1 or SHP-2, which dephosphorylate downstream kinases and inhibit key activation pathways, including those mediated by SYK, SRC, ZAP-70, and PI3K. Additionally, CSK, another negative regulator of SRC family kinases, can bind to LILRB1 and further enforce its inhibitory function.

This inhibitory axis leads to a range of immune suppressive effects, such as:

• Inhibition of T cell proliferation and cytotoxic activity
• Suppression of NK cell-mediated cytotoxicity
• Inhibition of antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis
• Transmission of "don’t eat me" signals that prevent macrophages from engulfing target cells

These immunosuppressive functions of LILRB1 not only maintain immune homeostasis but also allow tumors to evade immune surveillance, particularly by exploiting the HLA class I: LILRB1 interaction.

LILRB1 in Tumor Immunology

The overexpression of LILRB1 in various tumor environments has been well-documented. In particular:

• Certain acute myeloid leukemia (AML) cells express LILRB1, using it as a protective mechanism against apoptosis.
• Human gastric cancer cells exhibit high levels of LILRB1 expression, which is believed to promote tumor growth.
• LILRB1, by binding to HLA-G and other HLA class I molecules on tumor cells, delivers inhibitory signals that suppress NK cell and T cell activation, contributing to an immunosuppressive tumor microenvironment.

These features make LILRB1 a promising therapeutic target in oncology, especially for patients who are unresponsive to other immune checkpoint therapies like PD-1/PD-L1 inhibitors.

Drug Development Targeting LILRB1

The therapeutic potential of LILRB1 blockade lies in reversing its inhibitory effects on immune effector cells. A prominent example is the monoclonal antibody BND-22, which specifically targets LILRB1 and disrupts its interaction with HLA-G. By doing so, BND-22:

• Enhances the phagocytic activity of macrophages
• Promotes NK cell-mediated cytotoxicity
• Boosts T cell activation and expansion

Preclinical studies have demonstrated that blocking LILRB1 can significantly restore immune cell function in the tumor microenvironment. Importantly, compared to other LILRB family targets, LILRB1's broader expression across both innate and adaptive immune compartments gives its inhibitors greater therapeutic reach, particularly in tumors with complex immune evasion strategies.

Another noteworthy strategy is the dual blockade of LILRB1 and CD47. CD47 interacts with SIRPα to deliver a "don’t eat me" signal similar to the LILRB1 pathway. When combined, anti-LILRB1 and anti-CD47 antibodies can synergistically promote macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) of tumor cells. This approach has been tested using engineered antibodies with silenced Fc regions to avoid off-target immune activation and improve safety.

Moreover, dual-specific antibodies that target both LILRB1 and LILRB2 are under development. LILRB2, although more myeloid-restricted, shares structural similarity with LILRB1. Antibodies that bind to both receptors may offer broader inhibition of HLA class I-mediated suppression in myeloid cells, further enhancing antitumor immune responses.

Mechanistic Insights and Clinical Considerations

Mechanistically, LILRB1 signaling involves phosphorylation of specific tyrosine residues, such as Y533, Y562, Y614, and Y644, which are key docking sites for SHP-1 and SHP-2. Among these, Y614 is the main site for SHP-1 recruitment. The involvement of CSK in binding to Y562 adds another layer of signal inhibition, particularly in the SRC kinase pathway. Interestingly, in certain contexts, LILRB1 has also been shown to exert stimulatory effects, possibly via a mechanism involving a C-terminal immunotyrosine-based switch motif (ITSM), though this function remains less well-understood.

From a therapeutic standpoint, Fc engineering of anti-LILRB1 antibodies has become a critical aspect of drug development. While conventional IgG1 antibodies have strong Fcγ receptor (FcγR) binding and can induce ADCC or complement-dependent cytotoxicity (CDC), newer therapeutic antibodies are often based on Fc-silent formats (such as IgG4 or modified IgG1) to minimize off-target effects and avoid depleting LILRB1-expressing immune cells.

In clinical combination therapy strategies, LILRB1 antagonists are being considered alongside tumor-targeting antibodies like anti-CD20 (rituximab, obinutuzumab) and immune checkpoint inhibitors to enhance overall treatment efficacy. This multi-pronged approach aims to reactivate suppressed immune cells while targeting tumors directly, thereby overcoming resistance in solid tumors and hematological malignancies.

Future Prospects

The LILRB1 checkpoint pathway represents a novel and versatile target in cancer immunotherapy. As research continues to uncover the nuanced roles of this receptor in immune regulation and tumor escape, it becomes increasingly evident that LILRB1 blockade can complement existing therapeutic modalities and offer new hope for patients who do not benefit from current immunotherapies.

Moreover, the development of bispecific antibodies, fusion proteins, and combination regimens tailored to the LILRB1-HLA axis will likely expand the therapeutic arsenal against immune-resistant cancers. Considering its broad expression and dual role in modulating both innate and adaptive immunity, LILRB1 stands out as a key immune checkpoint with significant clinical translation potential.