The advantage of the avidin-biotin system is that antibody-streptavidin or antibody-biotin conjugates are easily developed. In addition, available biotin derivatives may be readily radiolabelled. Although the published results are impressive, problems related to the immunogenicity of avidin and streptavidin have not been solved. Bispecific antibodies may be prepared by a variety of techniques. In the early days, chemical conjugates of antibody fragments were used Stickney et al. The presence of excess bispecific antibody in the circulation at the time of radiolabelled hapten injection was a problem, and resulted in relatively slow activity clearance and non-specific deposition in normal tissues.
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Increasing the time delay between the two injections resulted in poor tumour activity uptake. This used a bivalent hapten that could cross-link bispecific antibody molecules at the surface of target cells and bind with enhanced affinity or avidity , whereas, in the circulation, binding remained rapidly reversible, avoiding the need for a chaseof excess bispecific antibody.
The interest of using bivalent haptens was independently confirmed by Goodwin and co-workers Goodwin et al. In the original studies performed by our group in association with the French company Immunotech Marseille, France , the bispecific antibody was prepared by chemical conjugation of the Fab fragment of the anti-CEA antibody F6 to the Fab fragment of an antibody recognizing the indium-DTPA complex. The bivalent hapten was prepared by reacting tyrosyl-lysine with DTPA anhydride. This bivalent hapten could be labelled with indium, but also radio-iodinated.
However, the antibody specificity for the indium-DTPA complex limited radiolabelling to indium or radioactive iodine. Bispecific antibodies recognizing another hapten, the histidine-succinyl-glycine HSG pseudo-peptide, were prepared and tested successfully with bivalent HSG haptens labelled with a variety of radionuclides Janevik-Ivanovska et al. Clinical AES pretargeted imaging using indium scintigraphy produced high contrast images Le Doussal et al.
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The development of FDG-PET imaging further limited the interest of pretargeting even if the specificity was very high. AES pretargeting could increase the radioimmunotherapy therapeutic index because it increases the tumour-to-normal tissue uptake ratio and increases radiation doses delivered to tumour cells. This was shown in preclinical models Gautherot et al. Haematological toxicity was the dose-limiting toxicity and the maximum tolerated activity was relatively low 1.
These patients were stratified according to calcitonin and CEA doubling times. Toxicity was mainly haematological, partly because of the frequent diffuse bone marrow tumour involvement. Interestingly, no other toxicity, especially renal toxicity, was reported. These results were confirmed in a prospective multicentric phase II trial.
After RIT, 21 of 37 assessed patients Hematologic toxicity grade 3 and 4 was observed in Recently, antibodies labelled with positron-emitters have been tested for PET imaging. Because of the slow pharmacokinetics of these antibodies, ong half-life positron emitters, such as zirconium half-life: Antibodies labelled with copper also provide good contrast images, but a shorter time interval is necessary because of the short radionuclide half-life In addition, the imaging procedure cannot be performed within a single day after activity injection.
Pretargeting could improve the performance of immuno-PET and allow for the use of short half-life positron-emitting radionuclides such as gallium or fluorine that would reduce patient irradiation. A few years ago Immunomedics Inc. These consist of the regulatory subunits of cAMP-dependent protein kinase fused with one antibody Fab fragment, and the anchoring domains of A kinase fused with the other Fab fragment This allows a very efficient production of bispecific trivalent antibodies, with one site binding the hapten and two sites binding the tumour antigen.
In addition, using the histamine-succinyl-glycine HSG pseudo-peptide allowed construction of a new bivalent hapten, IMP, permitting a variety of radionuclides to be used Sharkey et al. In preclinical experiments, high contrast PET images could be obtained within an hour after radiolabelled hapten injection using gallium and fluorine McBride et al. Extremely small tumours could be detected in mice.
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Preliminary imaging results were very promising in the three tumours as shown for a breast cancer patient in Fig. PET imaging of a patient with metastatic breast carcinoma. High activities of Lu-labelled IMP 2. Calculated radiation doses delivered to the kidneys and red bone marrow were relatively low Schoffelen et al. The therapeutic results were disappointing because of the relatively fast wash-out of tumour activity that limited tumour absorbed doses, especially with the long half-life lutetium Short half-life radionuclides and particularly short half-life alpha-particle-emitting radionuclides, such as astatine or bismuth, are considered for therapy, using both the avidin-biotin Yao et al.
In addition to the avidin-biotin and bispecific antibody approaches, two other alternatives have been proposed. The first relies on using the recognition between complementary DNA sequences. An antibody is derivatized with one oligonucleotide and the radioactivity is carried by an oligonucleotide of complementary sequence.
This approach was proposed by Bos and co-workers Bos et al. The other more recent approach is based on bio-orthogonal chemistry using the inverse-electron-demand Diels—Alder reaction between a tetrazine and a strained trans-cyclooctene TCO derivative. Rossin and co-workers first demonstrated that this reaction was fast enough and specific to be effective in vivo at the very low concentrations involved in cell targeting Rossin et al.
In this seminal paper, a proof of concept of specific tumour uptake was achieved, but the tumour to normal tissue ratios were modest Rossin et al.
Radiolabeled Monoclonal Antibodies for Imaging and Therapy
Similar biodistribution results were obtained in another system that also showed positive PET imaging Zeglis et al. In a recent paper, Hougton et al. Whilst the activity accretion in tumours was high the circulating activity was also high and declined slowly. To solve this problem, Rossin and co-workers used a chase step that considerably improved tumour uptake and tumour to non-tumour ratios Houghton et al.
As with the avidin-biotin system, the use of a chase step could therefore be a solution, but would be rather cumbersome with a risk of immunogenicity and hypersensitivity side-effects.
High tumour uptake 6. Tumour accretion and clearance of the pretargeting agent were fast enough to establish a large difference between the amount of Affibody bound to the tumour and that remaining in the circulation. The same Affibody was also used with very good pretargeting results using the oligonucleotide or peptide nucleotide in that case approach Honarvar et al. Further studies will show whether this promising approach can overcome the current limitations of pretargeting.
Pretargeting originated in the mids, and has been implemented in several different ways and tested in preclinical models and clinical trials.
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Despite highly promising results in preclinical tumour models, as well as in early phase clinical trials, pretargeting has not yet come close to market approval. However, pretargeting remains as potentially the ultimate theranostic, combining PET imaging with short-lived positron emitters and therapy with radionuclides emitting beta or alpha particles. Producing the required humanized recombinant immunoconjugates remains a challenge. Quadromas and chemically-coupled bispecific antibodies are difficult and expensive to prepare under GMP conditions and may not have the required purity for clinical development.
DNL TM bispecific antibodies proved very efficient for imaging, but not as effective for therapy. Bispecific diabodies and triabodies that appear very appropriate in terms of molecular weight and stability Rossi et al. Adaptation of older approaches that use avidin biotin or bispecific anti-tumour x anti-hapten antibodies with pretargeting using in vivo click chemistry show promise.
The use of small binding proteins for pretargeting may also offer a new perspective. Indeed, these binding proteins have fast in vivo kinetics, but tend to deliver very high activity to the kidneys as do most peptides , when radiolabelled with metal radionuclides. Pretargeting could be a way to overcome the problem and provide a new targeting approach for both imaging and therapy. Pretargeting is also one way to use short-lived radionuclides to image and treat cancers that do not over-express receptors or enzymes that could be targeted with small peptides or inhibitors.
In conclusion, pretargeting remains quite attractive, particularly for PET imaging and therapy, in a theranostic perspective. However, it requires careful optimization, both for the design of the appropriate pretargeting reagents, bispecific immunoconjugates binding tumour antigens and the small molecule selected to carry the activity, and for the definition of dosing and administration schedules. Full-scale clinical development programs remain needed to translate pretargeting into a clinical reality. J Nucl Med. Cure of human carcinoma xenografts by a single dose of pretargeted yttrium with negligible toxicity.
Pretargeting of renal cell carcinoma: improved tumor targeting with a bivalent chelate. Cancer Res. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol. Therapeutic Immunoconjugates. Current Cancer Ther Rev.
Pretargeting of cancer - Nuclear Medicine
Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma. Pretargeted radioimmunotherapy of colorectal cancer metastases: models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide. Pretargeted radioimmunotherapy of human colorectal xenografts with bispecific antibody and I-labeled bivalent hapten.
A novel bispecific, trivalent antibody construct for targeting pancreatic carcinoma. Goldenberg DM. Perspectives on oncologic imaging with radiolabeled antibodies.
Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. Monoclonal antibodies as reversible equilibrium carriers of radiopharmaceuticals. Pretargeted immunoscintigraphy: effect of hapten valency on murine tumor uptake. Pharmacokinetics of pretargeted monoclonal antibody 2D Zevalin: the first radioimmunotherapy approved for the treatment of lymphoma. Expert Rev Anticancer Ther. Problems associated with radioimmunodetection and possibilities for future solutions.
Monoclonal antibody therapy
J Biol Response Mod. Alpha- versus beta-emitting radionuclides for pretargeted radioimmunotherapy of CEA-expressing human colon cancer xenografts. Investigations of avidin and biotin for imaging applications. Mol Cancer Ther. Optimization of radioimmunotherapy of solid tumors: biological impediments and their modulation. Clin Cancer Res. Bivalent hapten-bearing peptides designed for iodine pretargeted radioimmunotherapy. Bioconjug Chem. Bispecific antibody and bivalent hapten radioimmunotherapy in CEA-producing medullary thyroid cancer xenograft.
Targeting, toxicity, and efficacy of 2-step, pretargeted radioimmunotherapy using a chimeric bispecific antibody and I-labeled bivalent hapten in a phase I optimization clinical trial. A pretargeting system for tumor PET imaging and radioimmunotherapy. Front Pharmacol. Development and characterization of anti-renal cell carcinoma x antichelate bispecific monoclonal antibodies for two-phase targeting of renal cell carcinoma.
This bar-code number lets you verify that you're getting exactly the right version or edition of a book. Editors view affiliations Suresh C. Srivastava; Conference proceedings. Suresh C. Criteria for the Selection of Nuclides for Radioimmunotherapy Get this from a library! Topics covered included the production, purification, and fragmentation of monoclonal antibodies and The adjuvant case involves the use of I-labelled, humanized, anti-carcinoembryonic antigen cea mAb after salvage resection of colorectal metastases to the liver, where a doubling of median survival to 68 months was reported during long-term follow-up In the pre-targeting mode, the tumour is first targeted with a bi-specific antibody.
One arm of the antibody binds to the tumour antigen