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Development of novel 18F-biotin conjugates for imaging pre-targeted antigens with positron emission tomography (PET)

Reference	BB/F00494X/1
Principal Investigator / Supervisor	Dr Timothy Smith
Co-Investigators / Co-Supervisors	Maria Appleyard, Professor Alastair Thompson, Dr Laurent Trembleau
Institution	University of Aberdeen
Department	Biomedical Physics and Bioengineering
Funding type	Research
Value (£)	220,960
Status	Completed
Type	Research Grant
Start date	01/03/2008
End date	28/02/2010
Duration	24 months

Abstract

Radio-labelled antibodies and their derivatives e.g. diabodies have high antigen avidity so are frequently utilised in imaging abnormally expressed cell surface antigens in disorders such as cancer.18F is the most ideal, positron emitting nuclide, in terms of decay characteristics, for imaging using positron emission tomography (PET). However its short t1/2 (110min) precludes its use for direct labelling of antibodies and diabodies for imaging purposes due to their long blood clearance time of many hours, whilst the loss of non-cell bound activity is crucial to allow adequate target to background ratio to become high enough for the target to be visualised. A strategy that enables short-lived nuclides such as 18F to be used in antibody imaging is to pre-target the antigen with an antibody that is conjugated to the affinity molecule, streptavidin (this compound specifically binds to biotin with very high affinity). The antibody-streptavidin conjugate is injected into the patient. After a few days when the antibody has bound to target cell antigen and much of the unbound has cleared from the blood stream (this can be enhanced by injecting a clearance conjugate), a further injection of the imaging nuclide conjugated to biotin is administered as this is small it will be quickly cleared from the bloodstream so that only nuclide-biotin conjugates bound to the streptavidin-antibody-cell antigen complex will remain. Here we will produce novel biotin conjugates that can be rapidly and simply fluorinated with 18F for imaging pre-targeted cell antigens. The specific activity of the conjugates will be greatly enhanced over 18F-labeled molecules produced by conventional procedures. We will test the 18F-biotin conjugates using a well-established model for pre-targeting that has been utilised for 124I and 64Cu. We will also use the conjugates to image the HER-2 receptors (the target for the therapy antibody, Herceptin) pre-targeted with HER-2 affibody-streptavidin conjugate

Summary

Many disease states including cancer and inflammatory disorders exhibit abnormal expression of cell surface proteins including receptors. These can be targeted using antibodies and antibody fragments. By attaching radioactive atoms to the targeting antibody and tracking its place of accumulation, post-injection into a patient using a gamma camera or positron emission tomography (PET) scanner it is possible to diagnose and localise the pathology. Some major problems associated with antibody imaging derive from the fact that less than 1% of injected radiolabelled antibody localises on cellular antigens much of the remainder remains in the circulation gradually being excreted through the kidney. However, the loss of non-cell bound activity is crucial to allow adequate target to background ratio to become high enough for the target to be visualised and can take days. PET detects gamma rays produced when a positron collides with an electron resulting in annihilation producing two gamma rays 180 degrees apart using coincidence detection. The resolution achievable using PET and hence the clarity of the images, is highly dependent on the energy of the positron emitted and is characteristic of the radionuclide used to label the targeting molecule. By far the best resolution is achieved using the positron-emitter 18F as it emits the lowest energy positron emitter used in PET. 18F is also the most commonly produced positron-emitting nuclide by medical cyclotrons and so is the most readily available. However 18F has a half-life of only 110mins excluding its use as a radiolabel for direct antigen targeting with antibodies. A strategy that enables short-lived nuclides such as 18F to be used in antibody imaging is to pre-target the antigen with an antibody that is conjugated to the affinity molecule, streptavidin (this compound specifically binds to biotin with very high affinity). The antibody-streptavidin conjugate is injected into the patient. After a few days when the antibody has bound to target cell antigen and much of the unbound has cleared from the blood stream (this can be enhanced by injecting a clearance conjugate), a further injection of the imaging nuclide conjugated to biotin is administered. Since this conjugate is small it will be quickly cleared from the bloodstream so that only nuclide-biotin conjugates bound to the streptavidin-antibody-cell antigen complex will remain. In this study we will produce novel biotin conjugates which can be rapidly and simply fluorinated with 18F for imaging pre-targeted cell antigens. The specific activity of the conjugates will be greatly enhanced over 18F-labeled molecules produced by conventional procedures. We will test the 18F-biotin conjugates using a well-established model for pre-targeting that has been utilised for 124I and 64Cu. We will also use the conjugates to image the HER-2 receptors (the target for the therapy antibody, Herceptin) pre-targeted with HER-2 affibody-streptavidin conjugates.

Committee	Closed Committee - Engineering & Biological Systems (EBS)
Research Topics	Immunology, Technology and Methods Development
Research Priority	X – Research Priority information not available
Research Initiative	Technology Development Initiative 2 (TDRI2) [2007]
Funding Scheme	X – not Funded via a specific Funding Scheme

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