Integrins are cell adhesion and signaling proteins that play important roles in a wide range of biological functions. Currently, integrin-targeting drugs have been extensively developed in areas including cardiovascular disease, inflammatory bowel disease, multiple sclerosis, and dry eye disease.
Although integrins have been investigated as potential therapeutic targets for various cancers for over 25 years, effective cancer drugs targeting integrins are yet to be developed. Integrin drug design may now be at a tipping point as recent studies have highlighted multiple promising independent mechanisms of integrin therapy for cancer. In combination with discoveries in pharmacology and structural biology, researchers are likely to achieve breakthroughs in cancer therapy.
Emerging therapeutic opportunities for integrin inhibitors
Several integrin inhibitor drugs have already been marketed while many others are still in preclinical studies. Since 2015, there have been a total of six integrin inhibitor drugs (Table 1) that target four integrins, including αIIbβ3 (also known as glycoprotein IIb/IIIa), α4β7, α4β1, and αLβ2.
Three of these drugs are antibodies and three are small molecules. The intravenously administered RGD-binding integrin αIIbβ3 inhibitor, one of the first inhibitors developed, includes two small molecules Tirofiban and Eptifibatide as well as an antibody Abciximab. All three therapies target acute coronary syndrome and cardiovascular thrombotic events. In addition, integrin αLβ2 is targeted by a marketed small molecule, Lifitegrast, for topical treatment of dry eye disease, and αLβ2 inhibitors are also being investigated for autoimmune and inflammatory diseases.
Other integrin drugs on the market, Vedolizumab and Natalizumab, are antibodies that primarily act on leucointegrin α4β7 and α4β1 for the treatment of ulcerative colitis, Crohn’s disease, and multiple sclerosis. Combined sales of the two molecules have exceeded 4 billion dollars annually, highlighting the role integrin inhibitors play in the treatment of various diseases.
Currently, two oral α4β7 antagonists are being tested clinically: a small molecule from Morphic Therapeutics (at stage I) and a peptide from Proteovant Therapeutics (at Stage II).
Other novel molecules targeting αv-containing integrins are currently entering clinical trials for fibrous dysplasia, including idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH), where there is a growing unmet medical need.
Since integrin proteins are key to many biological pathways and they bind to a large number of endogenous ligands, inhibition of a single integrin or family of integrins can treat a range of diseases, such as multiple fibrous diseases or cancers.
Targeting Integrins for Cancer Therapy — three mechanisms
Historically, the development of targeted integrin cancer drugs has focused on the RGD-binding integrin family. αvβ3, which has shown positive effects in preclinical models, remains the most commonly studied integrin over the past two decades. However, these studies failed to be converted into the clinic.
Fortunately, recent research has found three promising independent mechanisms by which integrins treat cancer: reducing PD-L1 expression in cancer cells, reducing TGF-β levels in the tumor microenvironment, and targeting integrins in T cells to enhance cytotoxicity and permeability.
- Integrins are involved in the regulation of PD-L1 expression and are therefore an important component of immune escape. αvβ3 actively regulates the expression of PD-L1 in the tumor microenvironment. In mouse studies, the absence of αvβ3 restricts the growth of primary tumors, which is especially important since most cancer patients treated with anti-PD-1 or anti-PD-L1 do not respond to the treatment. Anti-αvβ3 therapy may sensitivities tumors to the destruction of this axis, so combination with PD-1 or PD-L1 targeting drugs appears to be effective.
- Similar to αvβ3, blocking αvβ8 enhances cytotoxic T cell responses in tumors. In contrast to αvβ3, αvβ8 expression in tumors is usually not associated with PD-L1 expression. αvβ8 promotes tumor development through a different mechanism than αvβ3, which may involve TGF-β. In this alternative mechanism of immune escape, active TGF-β is released from its latent form present on immune cells by binding to αvβ8 on tumor cells or potential immune cells. Active TGF-β in the tumor stroma protects the tumor from T cells attack by preventing them from penetrating the tumor.
- Improving T cell adhesion and activation by targeting integrins is also a mechanism of action. Allosteric activation of the small molecule 7HP349 on leukocyte-specific integrins αLβ2 and α4β1 in T cells enhances T cell activation and adhesion, thereby improving T cell penetration into tumors in mouse models of melanoma and colon cancer. This compound is currently in phase I trial.
To date, research work has focused on RGD-binding approaches for the targeted delivery of drug bindings to tumors. SGN-B6A is an integrin-targeted ADC that recognizes β6 to selectively target solid tumors and is in Phase I clinical trial (NCT04389632).
Besides, BJ001, an integrin-targeted IL-15 fusion protein, has the potential to reduce systemic toxicity and enhance efficacy by targeting αvβ3, αvβ5, and αvβ6, which are highly expressed in tumors. The β7 subunit, which binds to a number of tumor cell antigens, can also target multiple myeloma using CAR T-cell approaches.
Is there a future for integrins as targets for tumor drugs?
Although integrins have experienced some setbacks as targets for tumor drug development, a recent understanding of their new mechanisms has led to renewed interest in them. The future integrin-targeting programs are supposed to focus on developing molecules that can adequately test mechanisms, robust target validation, clinical studies that measure target engagement, and the development of biomarkers to measure clinical efficacy.
BOC Sciences, as a competitive chemical manufacturer, has also invested substantial manpower and resources in the development of integrin inhibitors. The vast catalog is now available for both research institutes and industrial firms. With the dedication to superior quality and a stable supply of integrin inhibitors, BOC Sciences holds the vision of boosting cancer drug development targeting integrins.
Reference
1. Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov. 2021 Sep 17 : 1–19.