Tumour-targeting properties of antibodies specific to MMP-1A, MMP-2 and MMP-3.
OBJECTIVE
Matrix metalloproteinases (MMPs), a group of more than 20 zinc-containing endopeptidases, are upregulated in many diseases, but several attempts to use radiolabelled MMP inhibitors for imaging tumours have proved unsuccessful in mouse models, possibly due to the limited specificity of these agents or their unfavourable pharmacokinetic profiles. In principle, radiolabelled monoclonal antibodies could be considered for the selective targeting and imaging of individual MMPs.


METHODS
We cloned, produced and characterized high-affinity monoclonal antibodies specific to murine MMP-1A, MMP-2 and MMP-3 in SIP (small immunoprotein) miniantibody format using biochemical and immunochemical methods. We also performed comparative biodistribution analysis of their tumour-targeting properties at three time points (3 h, 24 h, 48 h) in mice bearing subcutaneous F9 tumours using radioiodinated protein preparations. The clinical stage L19 antibody, specific to the alternatively spliced EDB domain of fibronectin, was used as reference tumour-targeting agent for in vivo studies.


RESULTS
All anti-MMP antibodies and SIP(L19) strongly stained sections of F9 tumours when assessed by immunofluorescence methods. In biodistribution experiments, SIP(SP3), specific to MMP-3, selectively accumulated at the tumour site 24 and 48 h after intravenous injection, but was rapidly cleared from other organs. By contrast, SIP(SP1) and SIP(SP2), specific to MMP-1A and MMP-2, showed no preferential accumulation at the tumour site.


CONCLUSIONS
Antibodies specific to MMP-3 may serve as vehicles for the efficient and selective delivery of imaging agents or therapeutic molecules to sites of disease.
Pfaffen
Stefanie
S
Department of Chemistry and Applied Biosciences, ETH Zürich, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.
Frey
Katharina
K
Stutz
Irène
I
Roesli
Christoph
C
Neri
Dario
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000493:pharmacokinetics; D000918:Antibody Specificity; D003001:Cloning, Molecular; D020781:Matrix Metalloproteinase 1 / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000276:immunology; D019278:Matrix Metalloproteinase 3 / Q000276:immunology; D020782:Matrix Metalloproteinases / Q000276:immunology*; D051379:Mice; D057054:Molecular Imaging; D009369:Neoplasms / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1
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