Publications
231 results found
Kuyama J, McCormack A, George AJT, et al., 1997, Indium-111 labelled lymphocytes: Isotope distribution and cell division, EUROPEAN JOURNAL OF NUCLEAR MEDICINE, Vol: 24, Pages: 488-496, ISSN: 0340-6997
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- Citations: 41
Deonarain MP, RowlinsonBusza G, George AJT, et al., 1997, Redesigned anti-human placental alkaline phosphatase single-chain Fv: Soluble expression, characterization and in vivo tumour targeting, PROTEIN ENGINEERING, Vol: 10, Pages: 89-98, ISSN: 0269-2139
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- Citations: 22
Levy JB, Turner AN, George AJT, et al., 1996, Epitope analysis of the Goodpasture antigen using a resonant mirror biosensor, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 106, Pages: 79-85, ISSN: 0009-9104
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- Citations: 14
Huston JS, George AJ, Adams GP, et al., 1996, Single-chain Fv radioimmunotargeting., Q J Nucl Med, Vol: 40, Pages: 320-333, ISSN: 1125-0135
The availability of engineered antibody species has catalyzed new developments in radioimmunotargeting. This chapter summarized recent studies of single-chain Fv (sFv) proteins, which are minimal antibody binding sites engineered as single polypeptide chains. The single-chain Fv can be as small as 26 kDa monomers or may be engineered as larger fusion proteins designed to self-associate into dimeric or multimeric species. They typically exhibit rapid clearance that results in high targeting specificity within a matter of hours. We have compared different modes of administration to allow further manipulation of their biodistribution and targeting properties. Results of the present study comparing intravenous (i.v.) and intraperitoneal (i.p.) administration show comparable long-term retention in circulation, but the i.v. route showed an initially high peak blood level while i.p. injection did not. As with a single sFv dose, repeated bolus injections of sFv attained high target-to-background ratios, whereas continuous sFv infusion reached a steady state level of free sFv in blood and kidney that exceeded that in tumor xenografts. We observed improved localization of radioiodinated sFv in tumor xenografts if the radioiodine label resisted dehalogenation from the protein, which was accomplished, for example, through conjugation of a para-131I-benzoyl group to Iysyl epsilon-amino groups of the protein. Modification of the sFv by genetic incorporation of a cysteinyl peptide (to form sFv') provided a chelation site for radiometals that simplified incorporation of 99mTc with the opportunity for improved diagnostic imaging in cancer and other diseases. Therapeutic applications of sFv radioimmunotargeting could rely on sFv' complexed to 186Re or 188Re. Engineering sFv of sFv' with increased antigen-binding affinity and appropriately manipulating their mode of administration should promote sustained tumor retention conducive to clinically useful therapeutic indices.
George AJT, Ritter MA, 1996, Thymic involution with ageing: Obsolescence or good housekeeping?, IMMUNOLOGY TODAY, Vol: 17, Pages: 267-272, ISSN: 0167-5699
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- Citations: 269
George AJT, Ritter MA, Urch CE, 1996, Research training and Calman reforms: A role for the MSc?, POSTGRADUATE MEDICAL JOURNAL, Vol: 72, Pages: 321-322, ISSN: 0032-5473
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- Citations: 3
George A, Huston JS, Haber E, 1996, Exploring and exploiting the antibody and Ig superfamily combining sites, NATURE BIOTECHNOLOGY, Vol: 14, Pages: 584-584, ISSN: 1087-0156
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- Citations: 6
George AJT, Epenetos AA, 1996, Advances in antibody engineering, EXPERT OPINION ON THERAPEUTIC PATENTS, Vol: 6, Pages: 441-456, ISSN: 1354-3776
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- Citations: 9
Heelan BT, Thompson M, McCormack A, et al., 1996, The kinetics of MHC class I and class II expression in rat renal allografts., Transplantation, Vol: 61, Pages: 1274-1277, ISSN: 0041-1337
We have used in vivo localization of radiolabeled antibodies in a rat renal transplant model to compare the level of induction of major histocompatibility complex (MHC) class I and class II molecules in grafts undergoing rejection with grafts in which rejection was modified by cyclosporine (CsA). MHC class II expression increased in rejecting grafts, peaking on day 4, whereas a later rise in CsA-treated grafts was noted. The use of donor-specific antibodies demonstrated that this was due, in part, to a rise in class II of donor origin. No major differences in MHC class I levels were noted between the two groups until after day 4, when very little antibody localization was seen in the rejecting group. Our results suggest that therapeutic doses of CsA may not prevent the upregulation of class II that occurs during rejection, and that levels of class II are not of prognostic value in kidney transplantation.
Heelan BT, Thompson M, McCormack A, et al., 1996, The kinetics of MHC class I and class II expression in rat renal allografts - In vivo localization with radiolabeled antibodies, TRANSPLANTATION, Vol: 61, Pages: 1274-1277, ISSN: 0041-1337
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- Citations: 4
Larkin DFP, Oral HB, Ring CJA, et al., 1996, Adenovirus-mediated gene delivery to the corneal endothelium, TRANSPLANTATION, Vol: 61, Pages: 363-370, ISSN: 0041-1337
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- Citations: 107
Larkin DFP, Oral HB, George AJT, 1996, Adenovirus-mediated gene transfer to human cornea, Publisher: LIPPINCOTT-RAVEN PUBL, Pages: 4730-4730, ISSN: 0146-0404
George AJT, Jamar F, Tai MS, et al., 1996, Erratum: Radiometal labeling of recombinant proteins by a genetically engineered minimal chelation site: Technetium-99m coordination by single- chain Fv antibody fusion proteins through a C-terminal cysteinyl peptide (Proceedings of the National Academy of Sciences of the United States of America (August 29, 1995) 92:18 (8358-8362)), Proceedings of the National Academy of Sciences of the United States of America, Vol: 93, ISSN: 0027-8424
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- Citations: 1
Oral HB, George AJT, Haskard DO, 1996, Prevention of hydrogen peroxide- and cisplattn-induced apoptosis by catalase overexpression, Biochemical Society Transactions, Vol: 24, ISSN: 0300-5127
Programmed Cell Death (PCD) induced by H2O2 was investigated in Chinese Hamster Ovarian Cells (CHO), and compared to PCD induced by Cisplatin (25-50 μM), which is a well-known apoptosis- inducing agent. In preliminary experiments, CHO cells were treated with low concentrations of H2O2 (250-500 μM) continuously or for 3 hours followed by washing and further incubation in complete growth medium for I- 10 days. Fluorescence microscopy of acridine orangestained cells indicated morphological changes of PCD, including membrane Webbing, nuclear condensation and fragmentation. Similar changes were observed in cisplatin-treated cells. DNA laddering also revealed that DNA fragmentation began to occur in both adherent and non-adherent cells by day 2. To prevent H2O2-mediated PCD, the catalase gene was isolated and ligated into a mammalian expression vector (pCDM8). Transiently transfected cells contained approximately 17-fold increased catalase levels, as measured by ELISA. Overexpression of intracellular catalase provided protection of the CHO cells from H2O2 as measured by chromium-51 release and MTS assays. Furthermore, Cisplatin-mediated PCD was prevented by intracellular catalase Overexpression. The protective effect of catalase Overexpression on PCD induced by other agents is being investigated further.
Hornick P, George A, 1996, Blood contact activation: pathophysiological effects and therapeutic approaches, PERFUSION-UK, Vol: 11, Pages: 3-19, ISSN: 0267-6591
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- Citations: 26
Boleti E, Deonarain MP, Spooner RA, et al., 1995, Construction, expression and characterisation of a single chain anti-tumour antibody (scFv)-IL-2 fusion protein, ANNALS OF ONCOLOGY, Vol: 6, Pages: 945-947, ISSN: 0923-7534
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- Citations: 13
Boleti E, George AJT, Epenetos AA, 1995, Therapeutic monoclonals, 655th Meeting of the Biochemical-Society, Pages: 1044-1047
Boleti E, George AJT, Epenetos AA, 1995, Therapeutic monoclonals, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 23, Pages: 1044-1047, ISSN: 0300-5127
GEORGE AJT, JAMAR F, TAI MS, et al., 1995, RADIOMETAL LABELING OF RECOMBINANT PROTEINS BY A GENETICALLY-ENGINEERED MINIMAL CHELATION SITE - TC-99M COORDINATION BY SINGLE-CHAIN FV ANTIBODY FUSION PROTEINS THROUGH A C-TERMINAL CYSTEINYL PEPTIDE, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 92, Pages: 8358-8362, ISSN: 0027-8424
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- Citations: 66
George AJ, Jamar F, Tai MS, et al., 1995, Radiometal labeling of recombinant proteins by a genetically engineered minimal chelation site: technetium-99m coordination by single-chain Fv antibody fusion proteins through a C-terminal cysteinyl peptide., Proc Natl Acad Sci U S A, Vol: 92, Pages: 8358-8362, ISSN: 0027-8424
We describe a method to facilitate radioimaging with technetium-99m (99mTc) by genetic incorporation of a 99mTc chelation site in recombinant single-chain Fv (sFv) antibody proteins. This method relies on fusion of the sFv C terminus with a Gly4Cys peptide that specifically coordinates 99mTc. By using analogues of the 26-10 anti-digoxin sFv as our primary model, we find that addition of the chelate peptide, to form 26-10-1 sFv', does not alter the antigen-binding affinity of sFv. We have demonstrated nearly quantitative chelation of 0.5-50 mCi of 99mTc per mg of 26-10-1 sFv' (1 Ci = 37 GBq). These 99mTc-labeled sFv' complexes are highly stable to challenge with saline buffers, plasma, or diethylenetriaminepentaacetic acid. We find that the 99mTc-labeled 741F8-1 sFv', specific for the c-erbB-2 tumor-associated antigen, is effective in imaging human ovarian carcinoma in a scid mouse tumor xenograft model. This fusion chelate methodology should be applicable to diagnostic imaging with 99mTc and radioimmunotherapy with 186Re or 188Re, and its use could extend beyond the sFv' to other engineered antibodies, recombinant proteins, and synthetic peptides.
GEORGE AJT, FRENCH RR, GLENNIE MJ, 1995, MEASUREMENT OF KINETIC BINDING CONSTANTS OF A PANEL OF ANTI-SAPORIN ANTIBODIES USING A RESONANT MIRROR BIOSENSOR, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 183, Pages: 51-63, ISSN: 0022-1759
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- Citations: 93
George AJ, French RR, Glennie MJ, 1995, Measurement of kinetic binding constants of a panel of anti-saporin antibodies using a resonant mirror biosensor., J Immunol Methods, Vol: 183, Pages: 51-63, ISSN: 0022-1759
We have used a resonant mirror biosensor to determine the kinetics of binding of four antibodies, and their Fab' fragments, to their antigen, the plant-derived ribosome-inactivating protein (RIP) saporin. The analysis of the affinity of the antibodies was in reasonable agreement with values obtained by conventional techniques. However, the kinetic data showed that all four antibodies have a high dissociation rate constant (kdiss). These antibodies have been used in the construction of bispecific antibodies used to deliver saporin to tumour cells, and it is highly probable that the in vivo efficacy of the bispecific antibodies is limited by the high rate of dissociation of antibody-toxin complexes.
George AJ, Titus JA, Jost CR, et al., 1995, Redirection of cellular cytotoxicity. A two-step approach using recombinant single-chain Fv molecules., Cell Biophys, Vol: 26, Pages: 153-165, ISSN: 0163-4992
In this article the authors discuss an indirect system for redirecting cellular cytotoxicity, which utilizes a "universal" bispecific antibody to redirect T-cells to kill cells targeted with single-chain Fv (sFv) fusion proteins that carry a peptide tag recognized by the bispecific antibody. This approach has a number of theoretical advantages in the immunotherapy of cancer.
FRENCH RR, PENNEY CA, BROWNING AC, et al., 1995, DELIVERY OF THE RIBOSOME-INACTIVATING PROTEIN, GELONIN, TO LYMPHOMA-CELLS VIA CD22 AND CD38 USING BISPECIFIC ANTIBODIES, BRITISH JOURNAL OF CANCER, Vol: 71, Pages: 986-994, ISSN: 0007-0920
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- Citations: 30
GEORGE AJT, RITTER MA, LECHLER RI, 1995, DISEASE SUSCEPTIBILITY, TRANSPLANTATION AND THE MHC, IMMUNOLOGY TODAY, Vol: 16, Pages: 209-211, ISSN: 0167-5699
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- Citations: 8
George AJ, Ritter MA, Lechler RI, 1995, Disease susceptibility, transplantation and the MHC., Immunol Today, Vol: 16, Pages: 209-211, ISSN: 0167-5699
BARBONI E, RIVERO BP, GEORGE AJT, et al., 1995, THE GLYCOPHOSPHATIDYLINOSITOL ANCHOR AFFECTS THE CONFORMATION OF THY-1 PROTEIN, JOURNAL OF CELL SCIENCE, Vol: 108, Pages: 487-497, ISSN: 0021-9533
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- Citations: 70
GEORGE AJT, SPOONER RA, EPENETOS AA, 1994, APPLICATIONS OF MONOCLONAL-ANTIBODIES IN CLINICAL ONCOLOGY, IMMUNOLOGY TODAY, Vol: 15, Pages: 559-561, ISSN: 0167-5699
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- Citations: 17
JOST CR, KURUCZ I, JACOBUS CM, et al., 1994, MAMMALIAN EXPRESSION AND SECRETION OF FUNCTIONAL SINGLE-CHAIN FV MOLECULES, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 269, Pages: 26267-26273, ISSN: 0021-9258
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- Citations: 54
GEORGE AJT, TITUS JA, JOST CR, et al., 1994, REDIRECTION OF T-CELL-MEDIATED CYTOTOXICITY BY A RECOMBINANT SINGLE-CHAIN FV MOLECULE, JOURNAL OF IMMUNOLOGY, Vol: 152, Pages: 1802-1811, ISSN: 0022-1767
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- Citations: 51
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