Expression of αv integrins and vitronectin receptor identity in breast cancer cells

Meyer, Tim; Marshall, John F.; Hart, I. R.

doi:10.1038/bjc.1998.86

Cited by 78 publications

(78 citation statements)

References 21 publications

(20 reference statements)

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“…The two cell lines used, MDA-MB-435 and MDA-MB-231, are immortalized human breast cancer cell lines, and both cell lines express high levels of ␣ v ␤ 3 integrin (15,16). All cpAb constructs and control anti-integrin antibody LM609 bound efficiently to these cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Breaking the one antibody–one target axiom

Guo

Das

Mueller

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Studies at the interface of chemistry and biology have allowed us to develop an immunotherapeutic approach called chemically programmed antibodies (cpAbs), which combines the merits of traditional small-molecule drug design with immunotherapy. In this approach, a catalytic antibody catalyzes the covalent conjugation of a small molecule or peptide to the active site of the antibody, effectively recruiting the binding specificity of the conjugated molecule to the antibody. In essence, this technology provides the tools for breaking the ''one antibody-one target axiom'' of immunochemistry. Our studies in this area have focused on using the chemistry of the well studied aldolase catalytic antibodies of which mAb 38C2 is a member. Previously, we explored reversible assembly of cpAbs available through diketone chemistry. In this article, we explore a unique proadapter assembly strategy wherein an antibody 38C2-catalyzed transformation unveils a reactive tag that then reacts to form a stable covalent bond with the antibody. An integrin ␣v␤3 antagonist was synthesized with the designed proadapter and studied using human breast cancer cell lines MDA-MB-231 and MDA-MB-435. We demonstrate that this approach allows for (i) the effective assembly of cpAbs in vitro and in vivo, (ii) selective retargeting of 38C2 to integrin ␣v␤3 expressing breast cancer cell lines, (iii) intracellular delivery of cpAbs into cells, (iv) dramatically increased circulatory half-life, and (v) substantial enhancement of the therapeutic effect over the peptidomimetic itself in animal models of breast cancer metastasis. We believe that this technology possesses potential for the treatment and diagnosis of disease.catalytic antibody ͉ chemical programming ͉ combinatorial antibody libraries M onoclonal antibodies are a rapidly growing class of therapeutics for a wide variety of diseases (1, 2). Some of the advantages of antibodies include their relative lack of nonspecific toxicity, long half-life, and ease of access from patient-derived or synthetic combinatorial antibody libraries. For certain diseases, such as cancer, that antibodies can carry their own effector functions is of prime importance because the antibody specificity directs the killing function endemic to the effector domain, the Fc. It has always been axiomatic in immunochemistry that even though one may desire one or more of the advantageous properties common to all antibodies, due to their clonal nature, each task requires a different antibody. A solution to this problem, namely chemically programmed antibodies (cpAbs), has emerged at the interface of chemistry and biology: One can use different low-molecular-weight targeting agents (programming agents or adapters) to selectively target the same antibody to different sites for different uses (3). This strategy has the advantage that only a single antibody is required for a multiplicity of tasks, and it taps into the unlimited chemical diversity and the specificity that can be engendered by organic synthesis (4). The antibody provides ...

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Section: Resultsmentioning

confidence: 99%

Breaking the one antibody–one target axiom

Guo

Das

Mueller

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…We have shown that low intensity shear stress activates endothelial ELR ϩ CXC chemokine production via a HSPG/␤3- (43,44). Similar to our findings, FAK-induced p38 activation has been observed in cardiac myocytes, where mechanical stretch phosphorylates FAK to generate a binding site for grb2, a scaffolding protein that links FAK to the MAPK pathway (45).…”

Section: Discussionmentioning

confidence: 99%

Low Intensity Shear Stress Increases Endothelial ELR+ CXC Chemokine Production via a Focal Adhesion Kinase-p38β MAPK-NF-κB Pathway

Shaik

Soltau

Chaturvedi

et al. 2009

Journal of Biological Chemistry

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CXC chemokines with a glutamate-leucine-arginine (ELR) tripeptide motif (ELR؉ CXC chemokines) play an important role in leukocyte trafficking into the tissues. For reasons that are not well elucidated, circulating leukocytes are recruited into the tissues mainly in small vessels such as capillaries and venules. Because ELR ؉ CXC chemokines are important mediators of endothelial-leukocyte interaction, we compared chemokine expression by microvascular and aortic endothelium to investigate whether differences in chemokine expression by various endothelial types could, at least partially, explain the microvascular localization of endothelial-leukocyte interaction. Both in vitro and in vivo models indicate that ELR ؉ CXC chemokine expression is higher in microvascular endothelium than in aortic endothelial cells. These differences can be explained on the basis of the preferential activation of endothelial chemokine production by low intensity shear stress. Low shear activated endothelial ELR ؉ CXC chemokine production via cell surface heparan sulfates, ␤ 3 -integrins, focal adhesion kinase, the mitogen-activated protein kinase p38␤, mitogen-and stress-associated protein kinase-1, and the transcription factor.

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“…11 These cell lines and their derivatives were grown in OPTI-MEM medium (Invitrogen, Paisley, U.K.) supplemented with 10% fetal calf serum (FCS) without antibiotics.…”

Section: Cell Culture and Rna Transfectionmentioning

confidence: 99%