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G T Rogers

Publications and source records attributed to G T Rogers.

At least 19 recordsLinked to original sources
PubMed1997

The Ouchi illusion: an anomaly in the perception of rigid motion for limited spatial frequencies and angles.

The spatial parameters underlying a novel illusion of relative motion are characterized. A simple stimulus composed of two sine-wave gratings was sufficient to generate the illusion. We measured the response of subjects to rapid, small-amplitude oscillations of this stimulus behind a fixation point. The effect was clearly strongest for acute angles between the gratings, but only when spatial frequency was between 6 and 11 cpd. We surmise that activity in the grating cells of the primate visual cortex (von der Heydt, Peterhans, & Dursteler, 1992) might be the cause of the illusion. The illusion is potentially an important tool in understanding how higher cortical areas combine disparate motion signals.

Humans↗
PubMed1995

An illusion of relative motion dependent upon spatial frequency and orientation.

Observers scanned a stationary pattern comprising a tilted sine-wave grating completely surrounding another grating of similar spatial frequency but tilted in the opposite direction (Fig. 2). They reported an illusory "sliding" motion of the inset grating with respect to the surround grating and the effect was clearly strongest for angles between the gratings of less than 60 degrees and for spatial frequencies between 6-11 cpd. In a second experiment, a similar pattern was moved (2.0 deg/sec) either up or down for a presentation time of 167 msec. Simultaneously, the inset grating was drifted at different speeds in each of its two directions. Using the method of constant stimuli, it was shown that the relative motion illusion could be cancelled by physically drifting the grating in the opposite direction to the illusory movement. The illusion arises because there is a failure to integrate two motion signals into the single motion vector which characterises rigid motion.

Contrast Sensitivity↗
PubMed1995

Plasma clearance of an antibody--enzyme conjugate in ADEPT by monoclonal anti-enzyme: its effect on prodrug activation in vivo.

The effect of anti-enzyme antibody clearance on prodrug turnover in antibody-directed enzyme prodrug therapy (ADEPT) has been studied. Mice bearing LS174T xenografts were given localising carboxypeptidase G2 (CPG)2 conjugate (AEC) and 19 h later galactosylated anti-CPG2 antibody (SB43-GAL). In regimen I prodrug was injected 5 h after SB43-GAL as previously described. In regimen 2 and 3 a shortened and extended clearance time was used in which prodrug was administered 0.5 h or 53 h after SB43-GAL respectively. Regimen 1 resulted in similar tumour and normal tissue levels of active drug to those of the control in which prodrug was given 72 h after AEC. SB43-GAL therefore accelerated clearance of enzyme allowing early administration of prodrug. In regimen 2, very high active drug levels were found in the liver, showing removal of AEC from the blood followed by reactivation of enzyme and extensive and rapid prodrug turnover. Active drug levels in tumour and blood reached similar peak levels to those of the control. Regimen 3 resulted in lower active drug levels in tissues, consistent with degradation and excretion of enzyme. Regimen 3 also produced the best tumour to normal ratios for active drug. Residual prodrug in tumour was unaffected by SB43-GAL, showing the advantage of galactosylation in minimising inactivation of CPG2 in tumour. By contrast, residual prodrug in blood persisted for longer when SB43-GAL was used. Circulatory clearance of enzyme with SB43-GAL allows prodrug to be administered expediently with reduced toxicity and with the prospect of increasing the dosage.

Adenocarcinoma↗
PubMed1994

Galactosylated antibodies and antibody-enzyme conjugates in antibody-directed enzyme prodrug therapy.

Antibody directed enzyme prodrug therapy (ADEPT) has been studied as a two- and three-phase system in which an antibody to a tumor-associated antigen has been used to deliver an enzyme to tumor sites where it can convert a relatively nontoxic prodrug to a cytotoxic agent. In such a system, it is necessary to allow the enzyme activity to clear from the blood before prodrug injection to avoid toxicity caused by prodrug activation in plasma. To accelerate plasma clearance of enzyme activity, two approaches have been studied. The studies have been performed with a monoclonal anticarcinoembryonic-antigen antibody fragment A5B7-F(ab')2 conjugated to a bacterial enzyme, carboxypeptidase G2 (CPG2), in LS174T xenografted mice. In the first approach, a monoclonal antibody (SB43), directed at CPG2, was used, which inactivates CPG2 in vitro and in vivo. SB43 was galactosylated so that it had sufficient time to form a complex with plasma CPG2, resulting in the inactivation and clearance of the complex from plasma via the carbohydrate-specific receptors in the liver. Injection of SB43gal 19 hours after administration of the radiolabeled conjugate reduced the percentage of injected dose per gram in blood without affecting levels in the tumor. The second approach involved galactosylation of the conjugate so that it cleared rapidly from blood via the asialoglycoprotein receptors in the liver. Localization of the radiolabeled conjugate was achieved by blocking this receptor for about 8 hours with a single injection (8 mg/mouse) of an inhibitor that binds competitively to the receptor. This allowed tumor localization of the conjugate followed by a rapid clearance of the galactosylated conjugate from blood as the inhibitor was consumed. A tumor-to-blood ratio of 45:1 was obtained at 24 hours, which increased to 100:1 at 72 hours after the conjugate injection. These accelerated clearance mechanisms have been applied in antitumor studies in ADEPT.

Animals↗
PubMed1994

Antibody directed enzyme prodrug therapy (ADEPT). A review of some theoretical, experimental and clinical aspects.

The concept of generating cytotoxic agents from non-toxic prodrugs at tumour sites by antibody vectored enzyme introduces a wide range of opportunities. Various prodrug-enzyme combinations have been described and encouraging results reported in xenograft models. Whilst the mouse model is a valuable tool in this approach translation to the human patient may expose more complex issues. The objective of restricting drug action to tumour sites and thus allowing greatly increased cytotoxic action requires more precise restriction of enzyme activity to tumour sites than has been achieved with an antibody vector and natural clearance alone. Assisted clearance mechanisms have been found effective. Alternatively, or additionally, the difference between prodrug and active drug creates the opportunity to degrade active drug selectively in blood and thus protect normal tissues. In order to give more than one cycle of treatment it will be necessary for the antibody-enzyme conjugate to be nonimmunogenic or for the concurrent administration of immunosuppressive agents. A pilot scale clinical trial with a prototype prodrug indicated the feasibility of antibody directed enzyme prodrug therapy (ADEPT).

Animals↗
PubMed1993

Optimisation of small-scale coupling of A5B7 monoclonal antibody to carboxypeptidase G2.

Conjugates of F(ab')2 fragment of the monoclonal antibody A5B7 coupled to carboxypeptidase G2 (CPG2) have been produced using the heterobifunctional reagents 2-mercapto-[S-acetyl]acetic acid, N-hydroxysuccinimide ester (SATA) and m-maleimidobenzoyl-N-hydroxysuccinimide ester (SMPB). The effect of various levels of modifying reagent on enzyme activity and antigen binding activity were determined, and it was shown that whilst CPG2 is relatively sensitive to modification, insertion of three maleimide groups per CPG2 resulted in the loss of 30% of enzyme activity; A5B7 F(ab')2 was insensitive to modification, little or no activity being lost. The coupling efficiency of the reaction was shown to be fairly constant over a wide range of substitution levels. There was thus no advantage to be gained in using high substitution levels, which may result in loss of enzyme activity. The formation of undesired high molecular weight aggregates could be controlled by adjustment of the protein concentration during the final coupling step.

Antibodies, Monoclonal↗
PubMed1991

Ablation of human choriocarcinoma xenografts in nude mice by antibody-directed enzyme prodrug therapy (ADEPT) with three novel compounds.

Three novel prodrugs have been designed for use as anticancer agents. Each is a bifunctional alkylating agent which has been protected to form a relatively inactive prodrug. They are designed to be activated to their corresponding alkylating agents at a tumour site by prior administration of an antitumour antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in a two-phase system called antibody-directed enzyme prodrug therapy (ADEPT). The Km and Vmax values for three different antibody-CPG2 conjugates were determined in relation to each prodrug. The Km values ranged from 4.5-12 mumol/l and the Vmax from 0.5-1.6 mumol/U/min. Athymic Nu/Nu mice with palpable transplanted human choriocarcinoma xenografts, which are resistant to conventional chemotherapy, were treated with anti-human chorionic gonadotropin antibodies conjugated to CPG2. This was followed by each of the three novel prodrugs. Significant increase in survival was obtained in three of the regimens tested using only one course of treatment. This demonstrates the potential of a tumour-localised bacterial enzyme to activate protected alkylating agents in order to eradicate an established human xenograft.

Alkylating Agents↗
PubMed1990

Inactivation and clearance of an anti-CEA carboxypeptidase G2 conjugate in blood after localisation in a xenograft model.

Studies with a conjugate of carboxypeptidase G2 (CPG2) and the F(ab')2 fragment of monoclonal anti-CEA antibody, A5B7, have shown specific localisation in a human colon tumour xenograft, LS174T, growing in nude mice. The conjugate reaches a peak concentration in the tumour within 24 h but enzyme activity in blood remains above a critical value for therapeutic purposes for several days. Here we describe a new monoclonal antibody, SB43, raised against CPG2 which is capable of reducing enzyme activity in blood. In vitro studies demonstrated specific binding of SB43 to CPG2 causing inactivation. Moreover, in the nude mouse model SB43 was also capable of inactivating the enzyme in the circulation within minutes of administration. Radiolabelled native SB43 persisted in blood for several days and appreciable non-specific uptake into the xenograft was also observed. Uptake of SB43 by the tumour, with possible inactivation of CPG2 at this site, could be limited by first coupling the antibody to galactose. This ensured recognition and excretion of SB43 and SB43-enzyme complexes via the liver and their rapid removal from the circulation. Galactosylation had no effect on the ability of SB43 to inactivate the enzyme.

Animals↗
PubMed1990

Disposition of the prodrug 4-(bis (2-chloroethyl) amino) benzoyl-L-glutamic acid and its active parent drug in mice.

A novel therapy for improving selectivity in cancer chemotherapy aims to modify distribution of a cytotoxic drug by generating it selectively at tumour sites. In this approach an antibody-enzyme conjugate is allowed to localise at the tumour sites before injecting a prodrug which is converted to an active drug specifically by the targeted enzyme in the conjugate. We present here pharmacokinetic studies on the prodrug 4-(bis (2-chloroethyl) amino) benzoyl-L-glutamic acid and its activated derivative, benzoic acid mustard. The glutamic acid is cleaved from the prodrug to form the active drug by carboxypeptidase G2 (CPG2), an enzyme from Pseudomonas sp., which is not found in mammalian cells. The prodrug and its parent active drug were rapidly distributed in plasma and tissues after administration of prodrug or active drug (41 mumol kg-1 intraperitoneally) to mice bearing human choriocarcinoma xenografts. Prodrug and active drug both followed a two-compartment kinetic model. Prodrug was eliminated more rapidly (t1/2 alpha = 0.12 h, t1/2 beta = 0.70 h) than active drug (t1/2 alpha = 0.37 h, t1/2 beta = 1.61 h). Conversion of the prodrug to the activated parent drug was detected within 5 min of administration to mice which had previously received a F(ab')2-anti-human chorionic gonadotrophin antibody (W14A) conjugated to the enzyme, CPG2 (1,000 U kg-1). Tumour was the only tissue that activated all the prodrug reaching the site. It contained the highest concentration of targeted enzyme conjugate capable of catalysing the reaction of prodrug to drug. Plasma and other tissues were also capable of activating the prodrug but active drug production was limited by the amount of enzyme present. The active drug measured in plasma and tissues other than tumour was attributable to residual antibody-enzyme conjugate at non-tumour sites. Low levels of conjugate in tissues and plasma militate against the advantage of tumour localised enzyme therefore necessitating removal of non-localised enzyme.

Animals↗
PubMed1987

Relationship between tumour size and uptake of radiolabelled anti-CEA in a colon tumour xenograft.

The relationship between tumour size and the uptake of three radiolabelled anti-CEA localising antibodies (A5B7, 1H12 and PK2G) into a human colon tumour xenograft (MaWi) has been examined. For tumour weights greater than 100 mg (109-873 mg) there was a strong positive correlation between absolute uptake and tumour weight with mean uptakes per gram of 9.8 (r = 0.92), 5.0 (r = 0.93) and 5.3 (r = 0.94) for A5B7, 1H12 and PK2G respectively. For tumour weights below 100 mg (17-99 mg) the percentage uptake per gram (specific uptake) increased markedly reaching 80% of the injected dose for A5B7. The above phenomena could be modelled by representing uptake by the surface area of a sphere and tumour weight by its volume. Transformation of this model produced a linear relationship suitable for regression analysis of the experimental data. The slopes of the regression lines for the three antibodies were very close to that predicted by the model suggesting that their uptake into MaWi xenografts is proportional to surface area. The main discrepancy of the actual data was shown by the intercepts which relate to the variation in uptake between different antibodies. This model provides a possible means of correcting for the effect of tumour size when investigating the uptake of antibodies into xenografts.

Adenocarcinoma, Mucinous↗
PubMed1987

Significance of circulatory clearance of tumour-localising IgG and F(ab')2 for potential therapy studied in a CEA-producing xenograft model.

The significance of circulatory clearance of tumour-localising IgG and F(ab')2 for potential cancer therapy has been studied in immunodeprived mice bearing a carcinoembryonic antigen (CEA)-producing colon tumour. Intact radiolabelled anti-CEA (1H12) exhibited a prolonged localisation in tumour up to 8 days with injected doses between 4 and 256 g. Increased dosage caused a rise in the absolute concentration in tumour which, for the highest dose, reached 5.1 micrograms/g at 3 days after injection. A concomitant increase in concentration of 1H12 in blood occurred, which with the highest dose, remained above that in the tumour up to 7 days after injection. With F(ab')2 fragments (prepared from anti-CEA, 1C12) increased doses up to 380 micrograms also resulted in an increased uptake in tumour reaching almost 3 micrograms/g for a 234-micrograms dose. Circulatory clearance of F(ab')2-1C12 was essentially complete by 2 days for all doses up to 234 micrograms. Differences in clearance between 1H12 and F(ab')2-1C12 were reflected in the tumour to blood ratios. For high doses of 1H12 this ratio did not exceed unity up to 8 days. With F(ab')2, however, the tumour to blood ratio remained unaffected by dosage after 2 days. Our data suggest that F(ab')2 fragments clear sufficiently quickly to allow compensation by dosage for their premature escape from tumour. Therapeutic administration of intact antibody, however, appears to be limited by a protracted excretory process.

Animals↗
PubMed1986

Effect of dose escalation of a monoclonal anti-CEA IgG on tumour localisation and tissue distribution in nude mice xenografted with human colon carcinoma.

A monoclonal anti-CEA antibody (1H12) has been examined for the effect of dosage on tumour localisation in immunodeprived mice xenografted with human colon carcinoma. Increased doses produced a linear rise in the absolute concentration found in the tumour but this was found to depend on tumour size, with the smaller tumours (mean weight 44 mg) accumulating significantly more antibody compared to larger tumours (mean weight 146 mg). With the smallest tumour (18 mg), in which saturation was achieved, a 500 micrograms dose produced a concentration in tumour of 60 micrograms/g. In the larger tumours a dose of 256 micrograms produced a mean concentration of 5.2 micrograms/g. Prolonged retention of 1H12 by tumour up to 8 days, observed at doses of 4, 128 and 256 micrograms, indicated that the dynamics of localisation is unaffected by dosage. Increased doses of 125I-1H12 caused an increase in the levels of radioactivity associated with all normal tissues studied. Thus at 8 days after injection an increase from 4 to 128 micrograms produced 50% and 42% declines in the tumour to blood and liver ratios, respectively. Cumulative localisation of 1H12 in tumour, from 4 h to 8 days, relative to normal tissue clearance was diminished on increasing dosage. This study shows that attempted therapy with escalated amounts of intact antibody is likely to be limited by a protracted excretory process and measures aimed at accelerating circulatory clearance are necessary.

Animals↗
PubMed1986

Mapping epitope characteristics on carcinoembryonic antigen.

A method of epitope analysis is described in which the binding of one monoclonal antibody (MAb) to radiolabeled carcinoembryonic antigen (CEA) competes with the subsequent binding of an immobilised second MAb. From the degree of blocking obtained, we have identified both structurally related and independent epitopes on CEA. Using this technique to study fifteen MAbs, we have been able to recognise at least 6 unrelated epitopes of the CEA glycoprotein. Further characterisation of these epitopes was accomplished by means of immunohistochemistry. Of the fifteen MAbs, 6 were specific for CEA and reacted with at least 3 unrelated regions of the glycoprotein. Of the remaining 9 MAbs, 2 cross-reacted with erythrocytes, 5 with components of liver and 7 with polymorphonuclear neutrophils. Cross-reactions with liver were varied showing differential antibody specificity for bile canaliculi, Kupffer cells and bile duct epithelium. A high degree of correlation between epitope relatedness and immunohistochemical specificity was found. Two CEA-specific and 4 cross-reactive MAbs were also shown to react with ion-sensitive sites on the CEA glycoprotein.

Adenocarcinoma↗
PubMed1986

Dynamics of monoclonal antibody distribution and prolonged tumour localisation in nude mice bearing a human CEA-producing colon carcinoma xenograft.

A new monoclonal anti-CEA antibody (1H12) has been raised which has localising characteristics in a human colon tumour xenograft which could make it suitable for human immuno-radiotherapy. The amount of 1H12 localising in tumour reached about 5% of the injected dose by 7 hours. This rate appeared to be related to the concentration of 1H12 in the blood pool since non-excretory normal organs such as colon and stomach accumulated similar amounts up to 4 hours. Whereas 1H12 was lost from normal organs after 4 hours, the amount in the tumour continued to increase slightly reaching a maximum concentration of 6.5% of the injected dose by day 9. Prolonged retention of 1H12 in tumour enabled increasing tumour: normal tissue ratios to be attained during the residence time of the antibody thus providing scope for maximising the dose of radiation delivered to tumour cells. Preliminary dose escalation showed that up to 500 micrograms of 1H12 could be administered with increasing concentrations of antibody localising in tumour. Saturation of the tumour site was evident in only one mouse where 1.09 micrograms of 1H12 actually localised--equivalent to 60 micrograms per gram of tumour.

Animals↗