Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment
Abstract
:1. Introduction
2. Biology of the αvβ6 Integrin
2.1. Structure
2.2. Ligands
2.3. Expression
2.4. Regulation of Expression
3. Crosstalk with Growth Factors in General and Specifically with TGF-β
4. Implication of INGB6 in Cancer and Its Progression
5. Integrin αvβ6 as a Target for Imaging and Therapy
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Cancer | Functions |
---|---|
Endometrial | Promotes invasiveness [41] |
Basal Cell | Promotes invasiveness [42] |
Liver | Poor prognosis [43] |
Colon Cancer | Involved in cell adhesion and migration, activation of TGF-B, regulation of extracellular proteases, poor prognosis marker and implications in cancer metastasis to liver [43,44,45,46,47,48] |
Gastric | Prognostic marker [49] |
Cervical Squamous | Unfavourable marker [50] |
Oral SCC | Increased expression in invasive stage of the cancer, regulation of migration and adhesion of cancer cells [51,52,53] |
Pancreatic | Enhanced expression, regulation of tumour angiogenesis [54,55] |
Breast | EMT induction and invasiveness [56,57] |
Ovary | Enhanced expression leads to promotion of metastasis [58,59] |
Company | Target | Molecule ID/Name | Molecule Type | Drug Disease | Highest Status Reached | Summary |
---|---|---|---|---|---|---|
AstraZeneca | integrin subunit alpha V integrin subunit beta 6 | 264RAD | Antibody | Cancer, pancreatic | Preclinical, no active development reported. | 264RAD is a human therapeutic antibody targeting alphavβ6 integrin, which was under development by AstraZeneca for the treatment of pancreatic cancer. |
Aura Biosciences Cancer Research Technology | integrin subunit alpha V integrin subunit beta 6 | [19F] FAB-A20FMDV2; A20FMDV2; | Synthetic peptide | Cancer, pancreatic diagnosis, cancer | Preclinical, no active development reported. | A20FMDV2 is a lead integrin alphaVβ6 binding peptides, which was under development by Cancer Research Technology (CRT) for use in targeted delivery of anticancer compounds and for cancer imaging. |
Merck KGaA | integrin subunit alpha V integrin subunit beta 1 integrin subunit beta 3 integrin subunit beta 5 integrin subunit beta 6 integrin subunit beta 8 | Abituzumab | Antibody | Cancer, solid | Phase II, no active development reported. | Abituzumab is an investigational integrin inhibiting monoclonal antibody with activity against avβ1, 3, 5, 6, and 8 integrin heterodimers, which was under development by Merck KGaA for the treatment of colorectal cancer. It was previously developed for systemic sclerosis. |
Venn Therapeutics | integrin subunit alpha V integrin subunit beta 6 integrin subunit beta 8 transmembrane protein 173 | Ad-VCA0848; AdVCA0848; VTX 002; | Antibody | Cancer, unspecified. Chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis | Pre-clinical, no active development reported. | Ad-VCA-0848 (VTX-002) is a novel, immunotherapeutic off-the-shelf humanized monoclonal antibody STING agonist which recombined a potent diguanylate cyclase gene, VCA-0848, into a nonreplicating adenovirus serotype 5 targeting both alphavbeta8 and alphavbeta6, which was under development by Venn Therapeutics for the treatment of pulmonary fibrosis and COPD. It was previously under development for the treatment of cancer. |
GlaxoSmithKline | integrin subunit beta 6 | alpha v integrin antagonists, GlaxoSmithKline; avβ6 antagonists; avβ6 integrin anatagonists; integrin avβ6 anatagonists | Small molecule | Idiopathic pulmonary fibrosis | Preclinical, no active development reported. | GlaxoSmithKline was developing alpha v beta 6 integrin antagonists for the treatment of pulmonary fibrosis. |
DiCE Therapeutics | integrin subunit alpha V integrin subunit beta 1 integrin subunit beta 6 | alphaVbeta1/alphaVbeta6 integrin antagonist, DiCE Therapeutics; aVβ1/aVβ6 integrin antagonist, DiCE Therapeutics | Small molecule | Idiopathic pulmonary fibrosis | Preclinical, development active | DiCE Therapeutics (previously Dice Molecules) is developing an orally available alphaVbeta1/alphaVbeta6 (aVβ1/aVβ6) integrin antagonist using its DELSCAPE platform, for the treatment of idiopathic pulmonary fibrosis. |
Seagen | integrin subunit alpha V integrin subunit beta 6 | anti-alpha-V-beta6 ADC, Seattle; anti-avβ6 ADC, Seattle | Small molecule | Cancer, unspecified | Preclinical, no active development reported. | Seattle was developing a MAb against Integrin alpha-v-beta6, using its antibody–drug conjugate (ADC) technology, for the treatment of lung, pancreatic, and head and neck cancers. |
Cancer Research Technology Cancer Research Technology | integrin subunit alpha V integrin subunit beta 6 | anti-alphavβ6 antibodies, CRT; anti-integrin avss6 antibodies, CRT | Antibody | Cancer, unspecified; fibrosis, unspecified | Preclinical, no active development reported. | Cancer Research Technology (CRT) was developing anti-alphavβ6 antibodies for the treatment of cancer and fibrotic diseases. |
Biogen | integrin subunit alpha V integrin subunit beta 6 | alphav beta 6 integrin inhibitor, Biogen Idec; BG 00011; BG-00011; BG00011; STX-100; STX100 | Antibody | Cancer, unspecified; pulmonary fibrosis, nephropathy | Phase II clinical trials, no active development reported. | Biogen Idec (Stromedix) has discontinued development of BG-00011 (STX-100), a humanized mAb targeting the alpha v beta 6 integrin for the treatment of idiopathic pulmonary fibrosis (IPF), due to safety concerns. |
Panorama Research Corbus Pharmaceuticals | integrin subunit alpha V integrin subunit beta 6 integrin subunit beta 8 | CRB 602; CRB-602; CRB602 | Antibody | Cancer, unspecified; fibrosis, unspecified | Preclinical, development active | CRB-602 is an anti-alphavbeta6 and alphavbeta8 (avβ6/8) monoclonal antibody under development by Panorama Research in collaboration with Corbus Pharmaceuticals for the treatment of fibrosis and cancer. |
GlaxoSmithKline | integrin subunit alpha V integrin subunit beta 6 | alpha V beta 6 integrin antagonists, GlaxoSmithKline; GSK 3008348; GSK-3008348; GSK3008348 | Small molecule | Idiopathic pulmonary fibrosis | Phase I clinical trial, no active development reported. | GlaxoSmithKline has discontinued development of GSK-3008348, an alphaVbeta 6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis, due to a lack of confidence in developability and portfolio considerations following an interim analysis of Phase Ib data. It is an inhaled formulation. |
Indalo Therapeutics | integrin subunit alpha V integrin subunit beta 1 integrin subunit beta 3 integrin subunit beta 6 | Fibrotic disease therapy, Indalo Therapeutics; IDL 2965; IDL-2965; IDL2965 | Small molecule | Chronic renal failure, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis | Phase I clinical trial, no active development reported. | IDL-2965 is an oral, selective RGD-binding integrin (alphaVbeta1, alphaVbeta3 and alphaVbeta6) antagonist, which was under development by Indalo Therapeutics for the treatment of idiopathic pulmonary fibrosis and non-alcoholic steatohepatitis. RGD-binding integrin inhibits the activation of TGF-β as well as the ability of stiff extracellular matrix to promote fibroblast migration and survival. |
Centocor | integrin subunit alpha V integrin subunit beta 3 integrin subunit beta 5 integrin subunit beta 6 | BGB-101; BGB101; CNTO 95; CNTO-095; CNTO-95; intetumumab | Antibody | Cancer, solid | Phase II clinical trials, no active development reported. | Intetumumab is a high-affinity fully-human MAb, which was under development by Centocor (Johnson & Johnson (J&J)) for the treatment of cancer. It binds and inhibits integrins alphavβ1, alphavβ3, alphavβ5, alphavβ6 and alphavβ8, and has antiangiogenic activity It was generated using Medarex’s (now Bristol-Myers Squibb’s (BMS)) UltiMAb technology. |
AbbVie/Morphic Therapeutic | integrin subunit alpha V integrin subunit beta 6 | alphaVbeta6 small molecule inhibitor, Morphic Therapeutic; integrin therapies, Morphic Therapeutics; MORF 627; MORF beta6; MORF-627; MORF-beta6; MORF627; MORFbeta6 | Small molecule | Non-alcoholic steatohepatitis, Primary sclerosing cholangitis | Preclinical, no active development reported. | AbbVie has discontinued development of MORF-627 (MORF-beta6), an oral selective alphaVbeta6 small-molecule inhibitor licensed from Morphic Therapeutic, for the treatment of primary sclerosing cholangitis due to safety concerns. It was previously under development for non-alcoholic steatohepatitis. |
Morphic Therapeutic/AbbVie | integrin subunit alpha V integrin subunit beta 6 | MORF 720; MORF-720; MORF720 | Small molecule | Fibrosis, pulmonary, idiopathic | Preclinical, no active development reported. | AbbVie has discontinued development of MORF-720, an oral selective alphaVbeta6 small-molecule inhibitor, licensed from Morphic Therapeutic using its MlnT platform, for the treatment of idiopathic pulmonary fibrosis. |
Pliant Therapeutics | integrin subunit alpha V integrin subunit beta 1 integrin subunit beta 6 | avβ6/avβ1 dual integrin inhibitor, Pliant Therapeutics; PLN 1561; PLN-1561; PLN1561 | Small molecule | Primary sclerosing cholangitis | Preclinical, no active development reported. | PLN-1561 is an avβ6/aVβ1 dual integrin inhibitor, which was under development by Pliant Therapeutics for the treatment of primary sclerosing cholangitis. |
Pliant Therapeutics | integrin subunit alpha V integrin subunit beta 6 | aVβ6 inhibitor, Pliant Therapeutics; PLN 1705; PLN-1705; PLN1705 | Small molecule | Primary sclerosing cholangitis | Preclinical, no active development reported. | PLN-1705 is an aVβ6 selective inhibitor, which was under development by Pliant Therapeutics for the treatment of primary sclerosing cholangitis. |
Pliant Therapeutics | integrin subunit alpha V integrin subunit beta 1 integrin subunit beta 6 | avβ1/avβ6 dual integrin inhibitor, Pliant; avβ1/avβ6 integrin inhibitor, Pliant; PLN 74809; PLN-74809; PLN74809 | Small Molecule | Idiopathic pulmonary fibrosis, primary sclerosing cholangitis, COVID-19 complications, acute respiratory distress syndrome | Phase II clinical trial, active development reported. | PLN-74809 is an oral, small-molecule avbeta1/avbeta 6 dual integrin inhibitor under development by Pliant Therapeutics for the treatment of idiopathic pulmonary fibrosis and primary sclerosing cholangitis. The avβ1/avβ6 integrin blocks the activation of TGF-β in a tissue-specific manner, preventing the growth of fibrotic tissue within the lung. It was previously under development for acute respiratory distress syndrome (ARDS) associated with COVID-19. |
OcuTerra Therapeutics | integrin subunit alpha V integrin subunit beta 3 integrin subunit beta 6 integrin subunit beta 8 | OTT 166; OTT-166; OTT166; SF 0166; SF-0166; SF0166 | Small molecule | Retinopathy, diabetic macular degeneration, age-related, wet oedema, macular, diabetic | Phase II clinical trial, development active. | SF-0166 is a fluorinated, selective small-molecule inhibitor of integrin alphaVbeta3, alphaVbeta6 and alphaVbeta8, which is under development by SciFluor Life Sciences (now OcuTerra Therapeutics) for the treatment of diabetic retinopathy. It was previously in development for retinal disease, including wet age-related macular degeneration (AMD) and diabetic macular oedema (DME). It is administered topically to the eye. |
Seagen | integrin subunit beta 6 secretory leukocyte peptidase inhibitor | SGN B6A; SGN-B6A; SGNB6A | Small molecule | Cancer, solid, unspecified | Phase I clinical trial, development active. | SGN-B6A is an antibody-drug conjugate (ADC) targeting integrin beta-6, which is under development by Seagen (formerly Seattle Genetics) for the treatment of solid tumours. |
Ligand Pharmaceuticals | integrin subunit alpha 5 integrin subunit alpha V integrin subunit beta 1 integrin subunit beta 3 integrin subunit beta 5 integrin subunit beta 6 | XC 201; XC-201; XC201 | Recombinant peptide | Cancer, unspecified | Preclinical, active development reported. | XC-201 is a peptide-Fc fusion (mAb-lite) targeting avβ1, avβ3, avβ5, avβ6, and a5β1 integrins, which was under development by xCella Biosciences for the treatment of cancer. A unique engineered integrin-binding peptide is created, and it is genetically fused to an antibody Fc domain. It is a universal tumour targeting agent that binds a broad panel of integrins (av and a5) expressed at high levels on tumours. |
Title | Status | Conditions | Interventions | Locations | Phase | Reference |
---|---|---|---|---|---|---|
First-in-Human Positron Emission Tomography Study Using the 18FαVβ6-Binding-Peptide | Recruiting | Breast carcinoma|Colorectal carcinoma|Lung carcinoma|Metastatic malignant neoplasm in the breast|Metastatic malignant neoplasm in the colon|Metastatic malignant neoplasm in the lung|Metastatic malignant neoplasm in the rectum|Pancreatic carcinoma | Drug: 18F-αVβ6-BP | University of California Davis Comprehensive Cancer Center, Sacramento, California, United States | Early Phase 1 | https://ClinicalTrials.gov/show/NCT03164486, accessed on 10 October 2022 |
Phase 2a Evaluation of PLN-74809 on αVβ6 Receptor Occupancy Using PET Imaging in Participants With IPF/ | Recruiting | Idiopathic pulmonary fibrosis | Drug: PLN-74809|Radiation: Knottin tracer | Stanford Medical Center, Palo Alto, California, United States | Phase 2 | https://ClinicalTrials.gov/show/NCT04072315, accessed on 10 October 2022 |
PET/CT Imaging in COVID-19 Patients | Enrolling by invitation | COVID-19|SARS-CoV-2 Infection | Drug: 18F-αVβ6-BP | University of California Davis, Sacramento, California, United States | Early Phase 1 | https://ClinicalTrials.gov/show/NCT04376593, accessed on 10 October 2022 |
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Brzozowska, E.; Deshmukh, S. Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment. Int. J. Mol. Sci. 2022, 23, 12346. https://doi.org/10.3390/ijms232012346
Brzozowska E, Deshmukh S. Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment. International Journal of Molecular Sciences. 2022; 23(20):12346. https://doi.org/10.3390/ijms232012346
Chicago/Turabian StyleBrzozowska, Ewa, and Sameer Deshmukh. 2022. "Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment" International Journal of Molecular Sciences 23, no. 20: 12346. https://doi.org/10.3390/ijms232012346
APA StyleBrzozowska, E., & Deshmukh, S. (2022). Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment. International Journal of Molecular Sciences, 23(20), 12346. https://doi.org/10.3390/ijms232012346