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Inspiring Target: Integrin α4/β7 (LPAM-1)
Release time: 2023-03-15 Source: ACROBiosystems Read: 4776

Inspiring Target: Integrin α4/β7 (LPAM-1)

Integrin α-4/β-7, also known as Lymphocyte Peyer’s patch adhesion molecule-1 (LPAM-1), is an integrin heterodimer that is composed of covalently linked α-4 and β-7 subunits. LPAM-1is expressed on the surface of lymphocytes and acts as a homing receptor that mediates the adhesion of lymphocytes onto endothelial cells. Increased expression of LPAM-1 is found on memory CD4+ T cells near intestinal tissues. Furthermore, LPAM-1’s primary ligand is mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), a receptor specifically expressed on intestinal lamina venules and gut secondary lymphoid organs. As such, LPAM-1 plays a significant role in chronic gastrointestinal disorders and has been identified as a critical therapeutic target.

Inspiring Target: Integrin α4/β7 (LPAM-1)

Clinical Significance

Unsurprisingly, the interaction of LPAM-1 with MAdCAM-1 is heavily localized in the gastrointestinal area, mediating the transfer of immune cells in the gut.As such, most LPAM-1 targeted therapies are focused on relieving inflammation of gastrointestinal tissue stemming from disorders such as colitis, Crohn’s disease, or ulcerative colitis. Other diseases, such as HIV and graft-vs-host disease have also been implicated in gastrointestinal disfunction or also the use of related gut-associated lymphoid tissue as key sites for infection or activation, respectively.

Inflammatory Bowel Diseases

Inspiring Target: Integrin α4/β7 (LPAM-1)

Studies have shown that under the steady state the interaction of LPAM-1 and MAdCAM-1 enables T and B cells to enter the intestine. In inflammatory bowel diseases (IBD), T cells enter the intestine and contribute to chronic colonic inflammation. The inflamed mucosa from Crohn’s disease or ulcerative colitis also have an increased expression level of MAdCAM-1 to draw more immune cells towards the inflamed site.To combat this, antagonists to LPAM-1 have been developed to inhibit lymphocyte penetration into gut-associated lymphoid tissues.3

Human Immunodeficiency Virus (HIV)

Inspiring Target: Integrin α4/β7 (LPAM-1)

Recent research has identified that the HIV-1 glycoprotein can bind to LPAM-1. Due to interaction of MAdCAM-1 and LPAM-1, infected CD4+ cells with the HIV-1 virion are directed to the gut mucosa, leading to seeding and replication in the intestines during early infection. As such, targeting LPAM-1 for HIV prophylaxis has immense potential in developing a therapy against HIV. However,clinical results have been conflicting, with no clear correlation between HIV-1 infection and LPAM-1. 4

Graft vs Host Disease

Inspiring Target: Integrin α4/β7 (LPAM-1)

A major obstacle of tumor immunotherapy through bone marrow transplantation is graft-vs-host disease (GVHD). Normally, donor T cells upregulate expression of LPAM-1 as they infiltrate intestinal mucosa and differentiate into effector cells. Disruption of either LPAM-1 or MAdCAM-1 can reduce the amount of intestine-infiltrating donor T cells and helps alleviate intestinal injuries stemming from GVHD.5

Therapeutic Status of LPAM-1 Targeted Therapies

Currently, there are three approved therapies targeting LPAM-1 listed in Table 1. All of them are indicated for multiple uses focused on mitigating gut inflammations: This includes inflammatory bowel diseases, GVHD, and other types of cancers. HIV infections has also been indicated for Vedolizumab; however, understanding the pathogenesis of HIV is still lacking, thus providing mixed clinical evidence against HIV infections. With the acceptance of several integrin inhibitors for LPAM-1, integrins have been investigated thoroughly, with over 130 clinical trials being initiated since 2015. Out of the 24 known integrin heterodimers, only 6 have been accepted: 3 of them antibodies and the others as small molecules. The two approved LPAM-1 inhibitors, vedolizumab and natalizumab, has contributed to $4 billion USD per year, setting the stage for future integrin inhibitors.3

Table 1. Integrin α4/β7 marketed drug information

Inspiring Target: Integrin α4/β7 (LPAM-1)

Table 2. Drugs targeting Integrin α4 / β 7 in ongoing clinical trials

Inspiring Target: Integrin α4/β7 (LPAM-1)

Future Directions&Perspectives

What does this mean for LPAM-1 targeting therapeutics and integrin inhibitors in general? Overall, there are several directions that have been taken regarding integrins. The first is based on drug delivery: focusing on orally delivered therapies. This can help significantly expand the availability of integrin inhibitors. The second direction is focused on the inhibition of different integrins; most notably, αv-containing integrins to combat fibrotic diseases. These diseases, such as idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis have a significant and unmet medical need, making it an inspiring target. Similarly, since integrins play a pivotal role in cell signaling and transport, this family of molecule has the potential to treat a range of diseases, especially cancer.

To accelerate the research and development of integrin-targeting drugs, ACROBiosystems has a catalog of all 24 known integrin heterodimers, including integrin α4/β7, expressed through our HEK293 platform and verified by SEC-MALS.

References

1. ITGA4 - Integrin alpha-4 - Homo sapiens (Human) | UniProtKB | UniProt. https://www.uniprot.org/uniprotkb/P13612/entry.

2. ITGB7 - Integrin beta-7 - Homo sapiens (Human) | UniProtKB | UniProt. https://www.uniprot.org/uniprotkb/P26010/entry.

3. Slack, R. J., Macdonald, S. J. F., Roper, J. A., Jenkins, R. G. & Hatley, R. J. D. Emerging therapeutic opportunities for integrin inhibitors. Nat. Rev. Drug Discov. 21, 60–78 (2022).

4. Ueha, S. et al. Intervention of MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury while preserving graft-versus-tumor effects. J. Leukoc. Biol. 81, 176–185 (2007).

5. Liu, Q. & Lusso, P. Integrin α4β7 in HIV-1 infection: A critical review. J. Leukoc. Biol. 108, 627–632 (2020).

Inspiring Target: Integrin α4/β7 (LPAM-1)

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