The in vivo release of 90Y from cyclic and acyclic ligand-antibody conjugates

Harrison, A.; Walker, Carole A.; Parker, David; Jankowski, Karl J.; Cox, Jonathan P.L.; Craig, Andrew S.; Sansom, J. M.; Beeley, N. R. A.; Boyce, Rich; Chaplin, L; Eaton, Michael A. W.; Farnsworth, A. P.; Millar, Kenneth; Millican, Andrew T.; Randall, Amanda; Rhind, Stephen K.; Secher, D.S.; Turner, Alison

doi:10.1016/0883-2897(91)90107-v

Cited by 59 publications

(46 citation statements)

References 6 publications

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“…The stability of the attachment of radiochelate to antibody is an important determinant of therapeutic ratio, since some labelling methods, involving derivatives of the chelating ligand DTPA, produce relatively labile conjugates in vivo (Harrison et al, 1991). Weak ligands will lead to both a reduction in the amount of 90Y-conjugate in the tumour and irradiation of the normal tissues with free 90Y, especially proliferating tissues of the bone marrow, since 90Y is a boneseeking isotope (Hnatowich et al, 1983).…”

Section: Antigen Binding and Kinetic Analysismentioning

confidence: 99%

“…Weak ligands will lead to both a reduction in the amount of 90Y-conjugate in the tumour and irradiation of the normal tissues with free 90Y, especially proliferating tissues of the bone marrow, since 90Y is a boneseeking isotope (Hnatowich et al, 1983). The development of new chelating agents, such as the macrocyclic chelating agent DOTA (Moi et al, 1988;Cox et al, 1989), have proved to be more stable in vivo (Hird et al, 1991;Harrison et al, 1991). The cross-linkers used in this study contain the 12N4 DOTA macrocycle, which allows the site-specific attachment of 90Y and this has the added advantage that there is no loss of antigen binding after radiolabelling.…”

Section: Antigen Binding and Kinetic Analysismentioning

confidence: 99%

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Preparation, characterisation and tumour targeting of cross-linked divalent and trivalent anti-tumour Fab' fragments

Casey

King²,

Chaplin³

et al. 1996

Br J Cancer

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Summary The monoclonal anti-CEA antibody, A5B7, has previously been administered to patients for radioimmunotherapy (RIT). Long circulation time and the formation of an immune response have limited therapeutic success in the clinic. Antibody fragments can be used to reduce the in vivo circulation time, but the best combination of fragment and radioisotope to use for therapy is far from clear. In this study we have compared the biodistribution of A5B7 IgG and F(ab')2 with chemically cross-linked divalent (DFM) and trivalent (TFM) A5B7 Fab' fragments in nude mice bearing human colorectal tumour xenografts. The crosslinkers were designed to allow site-specific labelling using yttrium 90 (90Y), a high-energy f-emitter. We have also compared the above antibody forms conjugated to both 13'I and 9'Y. Both DFM and TFM were fully immunoreactive and remained intact after radiolabelling and incubation in serum at 37°C for 24 h. Biodistribution results showed similar tumour uptake levels and an identical blood clearance pattern for F(ab')2 and DFM with high tumour-blood ratios generated in each case. However, unacceptably high kidney accumulation for both F(ab')2 and DFM and elevated splenic uptake of DFM labelled with 9'Y was observed.Kinetic analysis of antigen binding revealed that DFM had the fastest association rate (kass = 1.6 x 105 Ms-1) of the antibody forms, perhaps owing to increased flexibility of the cross-linker. This advantage implies that DFM may be more suitable than F(ab')2 radiolabelled with 13'I for RIT. TFM cleared from the blood significantly faster than A5B7 IgG when labelled with both 13'I and 9'Y, producing an improved therapeutic tumour-blood ratio. Kidney accumulation was not observed for [90Y]TFM, but a slightly higher splenic uptake was observed that may indicate reticuloendothelial system (RES) uptake. Overall, tumour uptake was higher for 90Y-labelled antibodies than for '3'I-labelled antibodies. Because of the faster clearance, it should be possible to administer a higher total dose of 90Y-labelled TFM than IgG, which is attractive for RIT. Both A5B7 DFM and TFM, therefore, show favourable properties compared with their parent antibody forms.

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Section: Antigen Binding and Kinetic Analysismentioning

confidence: 99%

Section: Antigen Binding and Kinetic Analysismentioning

confidence: 99%

Preparation, characterisation and tumour targeting of cross-linked divalent and trivalent anti-tumour Fab' fragments

Casey

King²,

Chaplin³

et al. 1996

Br J Cancer

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“…Determination of affinities of murine and humanised antibodies was based on the procedure described by Krause et al (1990 Radiolabelling and animal studies Antibodies were labelled with 9Y via the macrocyclic ligand tetra-azocyclododecane tetra-acetic acid, (termed 12N4 or DOTA) coupled to the immunoglobulin via 12N4-maleimide linkers (Harrison et al, 1991) as previously described . Radiolabelling of hA33-12N4 conjugates with 9Y and 125I, and biodistribution studies in nude mice bearing subcutaneous SW1222 tumour xenografts were carried out also as described .…”

Section: Methodsmentioning

confidence: 99%

“…Attempts to circumvent this problem by the co-administration of free EDTA to chelate free 9Y released have also been made but showed only a very limited improvement (Stewart et al, 1990). Stable macrocyclic chelators for 9'Y have now been developed based on the macrocycle 12N4 (also known as DOTA), which essentially completely prevents loss of the isotope from the conjugate under physiological conditions (Deshpande et al, 1990;Harrison et al, 1991;DeNardo et al, 1994).…”

mentioning

confidence: 99%

Preparation and preclinical evaluation of humanised A33 immunoconjugates for radioimmunotherapy

King

Antoniw²,

Owens³

et al. 1995

Br J Cancer

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Summary A humanised IgGl/k version of A33 (hA33) has been constructed and expressed with yields up to 700 mg 1' in mouse myeloma NS0 cells in suspension culture. The equilibrium dissociation constant of hA33 (KD= 1.3 al., 1990, 1994). A phase I/II study has been conducted (Welt et al., 1994) with this murine antibody, in which some tumour responses were observed at the maximum tolerated dose (75 mCi m-2). The major limiting toxicity was haematological, as observed in almost all therapy studies with radioimmunoconjugates. All patients treated developed a human anti-mouse antibody (HAMA) response after one administration, and this led to very rapid clearance of the conjugate upon retreatment, consistent with all previous results with rodent antibodies. These data suggest that A33 is a promising antibody for successful radioimmunotherapy of colon cancer, and the purpose of this study has been to design and develop a second generation reagent based upon it. The key to the development of successful radioimmunotherapy will be the identification of reagents capable of delivering a killing dose to tumour cells without unacceptable toxicity to normal tissues. To this end we are evaluating several alternative radioimmunotherapeutic strategies including the use of isotopes which require internalisation into the cell for cytotoxicity, such as 125I (which are less toxic to normal tissues), and engineering the antibody for the optimal delivery of highly cytotoxic agents such as 90Y.The radioisotope 9'Y has been used in several radioimmunotherapy studies and is an attractive isotope for this purpose owing to its appropriate physical properties. As a pure high-energy P-emitter 9Y has advantages over the more

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“…Compound 12 as its HCl salt was reacted with tert-butyl bromoacetate in DMF at 90 °C to provide tert-butyl C-NETA 13 in 54% yield (Scheme 3). Compound 13 was further treated with 4 M HCl/1,4-dioxane to provide the desired bifunctional ligand C-NETA (14) in the nitro form.…”

Section: Resultsmentioning

confidence: 99%

Rational Design and Generation of a Bimodal Bifunctional Ligand for Antibody-Targeted Radiation Cancer Therapy

Chong

et al. 2007

J. Med. Chem.

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An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of 212 Bi, 213 Bi, and 177 Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. 177 Lu-C-NETA and 205/6 Bi-C-NETA possess an excellent or acceptable in vivo biodistribution profile.

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The in vivo release of 90Y from cyclic and acyclic ligand-antibody conjugates

Cited by 59 publications

References 6 publications

Preparation, characterisation and tumour targeting of cross-linked divalent and trivalent anti-tumour Fab' fragments

Preparation, characterisation and tumour targeting of cross-linked divalent and trivalent anti-tumour Fab' fragments

Preparation and preclinical evaluation of humanised A33 immunoconjugates for radioimmunotherapy

Rational Design and Generation of a Bimodal Bifunctional Ligand for Antibody-Targeted Radiation Cancer Therapy

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