The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αVβ3 Integrin via Steric Hindrance

Borst, Andrew J.; James, Zachary M.; Zagotta, William N.; Ginsberg, Mark H.; Rey, F.A.; DiMaio, Frank; Backović, Marija; Veesler, David

doi:10.1016/j.str.2017.09.007

Cited by 29 publications

(25 citation statements)

References 61 publications

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“…LM609 is a mouse mAb that specifically recognizes human integrin αvβ3 and inhibits angiogenesis [ 124 ]. It showed promising results for inhibiting angiogenesis, the tumor cell invasion ability and tumor growth in breast cancer and melanoma in the 1990s [ 38 , 125 ].…”

Section: Integrins As Targets For Melanoma Therapiesmentioning

confidence: 99%

Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma

Huang

Rofstad

2018

J Exp Clin Cancer Res

134

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Integrins are a large family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. Among the 24 integrin isoforms, many have been found to be associated with tumor angiogenesis, tumor cell migration and proliferation, and metastasis. Integrins, especially αvβ3, αvβ5 and α5β1, participate in mediating tumor angiogenesis by interacting with the vascular endothelial growth factor and angiopoietin-Tie signaling pathways. Melanoma patients have a poor prognosis when the primary tumor has generated distant metastases, and the melanoma metastatic site is an independent predictor of the survival of these patients. Different integrins on the melanoma cell surface preferentially direct circulating melanoma cells to different organs and promote the development of metastases at specific organ sites. For instance, melanoma cells expressing integrin β3 tend to metastasize to the lungs, whereas those expressing integrin β1 preferentially generate lymph node metastases. Moreover, tumor cell-derived exosomes which contain different integrins may prepare a pre-metastatic niche in specific organs and promote organ-specific metastases. Because of the important role that integrins play in tumor angiogenesis and metastasis, they have become promising targets for the treatment of advanced cancer. In this paper, we review the integrin isoforms responsible for angiogenesis and organ-specific metastasis in malignant melanoma and the inhibitors that have been considered for the future treatment of metastatic disease.

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Section: Integrins As Targets For Melanoma Therapiesmentioning

confidence: 99%

Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma

Huang

Rofstad

2018

J Exp Clin Cancer Res

134

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“…MEDI‐522 (Abegrin, etaracizumab, Vitaxin), another angiogenesis inhibitor, is a monoclonal antibody that targets integrin ɑvβ3. It was derived from the murine antibody LM609, 70 humanized and subsequently affinity maturated 71 . In a phase II clinical trial involving 112 participants with metastatic melanoma, MEDI‐522 (8 mg/kg/week) was shown to be well tolerated with or without dacarbazine (1,000 mg/m 2 once every 3 weeks).…”

Section: Integrin‐targeted Therapeuticsmentioning

confidence: 99%

The role of integrins in melanoma: a review

et al. 2020

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Integrins are the major family of cell adhesion receptors in humans and essential for a wide range of normal physiology, including formation and maintenance of tissue structure integrity, cell migration, proliferation, and differentiation. Integrins also play a prominent role in tumor growth and metastasis. Translational research has tried to define the contribution of integrins to the phenotypic aggressiveness of melanoma because such knowledge is clinically useful. For example, differential expression of integrins in primary cutaneous melanoma can be used to distinguish indolent from aggressive, prometastatic melanoma.Recent studies have shown that gene expression-based testing of patient-derived melanoma tissue is feasible, and molecular tests may fully replace interventional surgical methods such as sentinel lymph node biopsies in the future. Because of their central role in mediating invasion and metastasis, integrins are likely to be useful biomarkers. Integrins are also attractive candidate targets for interventional therapy. This article focuses on the role of integrins in melanoma and highlights recent advances in the field of translational research.

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“…Notably, none of these peptides affected the binding of the mAb LM609 (Figure C), an isotype‐matched monoclonal antibody capable of recognizing the headpiece region of α v β 3 in all integrin conformational states, the data indicating that the effects observed with AP5 were indeed related to conformational changes and not to changes in integrin expression.…”

Section: Resultsmentioning

confidence: 99%

The Importance of Detail: How Differences in Ligand Structures Determine Distinct Functional Responses in Integrin α_vβ₃

Paladino

Civera

Curnis

et al. 2019

Chemistry A European J

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Ligand‐based control of protein functional motions can provide novel opportunities in the study of fundamental biological mechanisms and in the development of novel therapeutics. In this work we addressed the ligand‐based modulation of integrin functions. Inhibitors of integrin αvβ3 are interesting anticancer agents but their molecular mechanisms are still unclear: Peptides and peptidomimetics characterized by the Arg‐Gly‐Asp (RGD) or isoAsp‐Gly‐Arg (isoDGR) binding motifs have shown controversial agonist/antagonist effects. We have investigated the differential mechanisms of integrin activation/deactivation by three distinct ligands (cyclo‐RGDf(NMe)V (Cilengitide), cyclo[DKP3‐RGD], cyclo[DKP3‐isoDGR]; DKP=diketopiperazine) through a comparative analysis of ligand‐controlled protein internal dynamics: Although RGD facilitates the onset of dynamic states leading to activation, isoDGR induces a diffuse rigidification of the complex consistent with antagonist activities. Computational predictions have been experimentally probed by showing that the antibody AP5, which is capable of recognizing the active form of integrin, binds specifically to the RGD complexes and not to the isoDGR complex, which supports opposite functional roles of the two motifs targeting the same binding site.

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The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αVβ3 Integrin via Steric Hindrance

Cited by 29 publications

References 61 publications

Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma

Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma

The role of integrins in melanoma: a review

The Importance of Detail: How Differences in Ligand Structures Determine Distinct Functional Responses in Integrin α_vβ₃

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The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αVβ3 Integrin via Steric Hindrance

Cited by 29 publications

References 61 publications

Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma

Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma

The role of integrins in melanoma: a review

The Importance of Detail: How Differences in Ligand Structures Determine Distinct Functional Responses in Integrin αvβ3

Contact Info

Product

Resources

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The Importance of Detail: How Differences in Ligand Structures Determine Distinct Functional Responses in Integrin α_vβ₃