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Biomedical subjects

M V Pimm

Publications and source records attributed to M V Pimm.

At least 55 records · Page 3Linked to original sources
PubMed1990

A passive haemagglutination test for human anti-mouse antibody (HAMA) responses in patients undergoing immunoscintigraphy.

Sera from seven patients with ovarian or colorectal carcinoma who had been given only single injections of 131I or 111In labelled IgG1, IgG2a or IgG2b monoclonal antibodies for immunoscintigraphy 2 weeks to 9 months earlier were tested for their ability to agglutinate sheep red blood cells coated with a mouse monoclonal antibody. Six showed agglutination, and this was still seen when sera were diluted to 1/125 in four patients and as low as 1/3125 in the other two. Sera from rats and mice which had been injected with monoclonal antibody also caused agglutination, which in the case of the mouse sera is due to the presence of anti-idiotypic antibody. This study shows that it is feasible to detect HAMA by a rapid, simple, passive haemagglutination reaction.

Animals↗
PubMed1989

The influence of syngeneic anti-idiotypic antibody on the biodistribution of an anti-tumour monoclonal antibody in BALB/c mice.

BALB/c mice were immunized against syngeneic murine 791T/36 monoclonal antibody (MAb) by intraperitoneal (i.p.) injection of the antibody conjugated to ricin toxin A chain. Subsequently, in these and control mice, the biodistribution of radioiodinated 791T/36 antibody and isotype-matched (IgG2b) control immunoglobulin was examined. Pre-treated mice showed marked perturbation of biodistribution of the 791T/36 antibody but not of control IgG2b. This was manifest as rapid hepatic clearance of the antibody which was followed by accelerated catabolism and excretion of the radiolabel. Anti-idiotypic antibodies were identified in immunotoxin pretreated mice by their ability to inhibit the binding of FITC-labelled 791T/36 antibody to tumour target cells. These studies show that antibody responses, even to only the idiotype of a MAb, may produce marked perturbation of its biodistribution. This has implications for the clinical use of human or chimeric MAbs for tumour imaging or targeting of therapeutic agents since, if anti-idiotypic antibodies are evoked, they could still prevent tumour localization of antibody or conjugate.

Animals↗
PubMed1989

Influence of circulating antigen on the biodistribution and tumour localization of radiolabelled monoclonal antibody in a human tumour: nude mouse xenograft model.

A monoclonal antibody, against a colorectal carcinoma tumour-associated antigen, was radioiodinated and its biodistribution studied in comparison with that of control immunoglobulin in nude mice with colon carcinoma xenografts. Tumour localization of the antibody in comparison with normal tissues was poor, and in absolute terms more control IgG than antibody was present per gram of tumour. This failure to achieve localization could not be ascribed to poor immunoreactivity of the antibody nor to the failure of the xenografts to express the appropriate antigen. Analysis of serum from mice with xenografts showed the presence of circulating tumour-derived antigen. This serum-borne antigen was found to form immune complexes both in vitro and in vivo with the monoclonal antibody, and this complex formation is probably the limiting factor in tumour localization of the antibody. This is one of only few examples where mice with human tumour xenografts have levels of circulating antigen sufficient to perturb biodistribution of antibody. These findings are relevant to the biodistribution of monoclonal antibodies in the clinical situation, since circulating antigen is often found in cancer patients.

Animals↗
PubMed1989

Intraperitoneal 131I- and 111In-791T/36 monoclonal antibody in recurrent ovarian cancer: imaging and biodistribution.

An examination of the biokinetics and biodistribution of i.p. administered 131I- or 111In-labelled 791T/36 antibody (1 mg) has been carried out in five patients with stage III/IV ovarian cancer. Blood kinetics and urinary excretion of the radiolabels were assayed. Scintigraphy was performed immediately following administration and before and after peritoneal lavage at 48 h. Blood levels of both preparations rose over the first 20-40 h reaching 8-14% of the administered dose in the circulation and then declined (T1/2 of 40 h). Circulating radiolabel was still attached partially to antibody as shown by precipitation with anti-mouse IgG antiserum. The rapid appearance of radiolabel in the bloodstream meant that any tumour localization could be from circulating antibody rather than local infiltration. Interpretation of the images was difficult and the distribution of the tracer was different from that previously observed using i.v. administration of antibody. In some cases the images were confusing and the uptake of activity did not fit in with the clinical knowledge of the disease or the findings from laparoscopy. Tumour specimens resected at 4-5 days showed up to 0.02% of the dose g-1.

Adult↗
PubMed1989

Blood and tissue kinetics of radiolabelled anti-CEA monoclonal antibody and F(ab)2 and Fab fragments in nude mice with human tumour xenografts: implications for tumour imaging and radioimmunotherapy.

The kinetics of a radiolabelled anti-CEA monoclonal antibody and its F(ab)2 and Fab fragments have been examined in mice including those with human tumour xenografts reactive with this antibody. With intact antibody the blood alpha phase half time was 9.9 h, the beta catabolic phase 128 h, with 55% of the remaining antibody in the intravascular compartment. Tumour localization was slow, peak levels of 22% of the dose g-1 being attained by 24 h, but remaining constant to at least 48 h. F(ab)2 fragments alpha and beta half times were 2.95 and 7.8 h, with an intravascular fraction of only 11%. Peak levels of tumour localization were seen within 7 h of injection but reached only 10% of the dose g-1 and then declined. Fab fragment half times were only 0.31 and 5.4 h, with 9% remaining intravascularly. Tumour localization was seen early but at only 2.5% of the dose g-1, and then declined. Tumour to blood ratios increased over time with all preparations, but reached only 2.5:1 with intact antibody compared with 15:1 and 19:1 with F(ab)2 and Fab respectively. These studies emphasize that the improved tumour: normal tissue ratios obtained with antibody fragments are the result of both faster and greater extravasation of fragments and their faster overall catabolism.

Animals↗
PubMed1988

Biodistribution and tumour localization of a methotrexate-monoclonal-antibody 791T/36 conjugate in nude mice with human tumour xenografts.

The blood kinetics and tumour localization of a conjugate of methotrexate (MTX) and MAb 791T/36 were examined in nude mice with human tumour xenografts. The antibody moiety of the conjugate was detected by labelling with 125I and the drug moiety was assayed using a radioimmunoassay for methotrexate. After radioiodination, the drug moiety was co-precipitable with the radiolabel when TCA or rabbit anti-mouse IgG antiserum was used. Following i.v. injection, serum kinetics of both the antibody and the drug moieties of the conjugate were essentially similar, and the integrity of serum-borne conjugate was confirmed by the co-precipitation of radiolabel and drug. The radiolabelled antibody moiety of the conjugate localized in tumour xenografts, with 5-7% of the injected dose being present per gram of tissue within 6 hr of injection, and the levels were maintained for up to 4 days. Analysis of tumour levels of the MTX moiety showed a progressive uptake over the 4-day observation period with up to 4% of the injected dose being present per gram of tumour when the experiment was terminated. Parallel studies with free MTX showed rapid clearance from the blood and a maximum of 0.35% of the dose/g of tumour 30 min after injection. Control immunoglobulin conjugated to MTX did not show tumour localization of either the antibody or the drug moieties. These studies confirm that in vivo MTX remains bound to antibody in this type of drug antibody conjugate and demonstrate site-specific targeting of this therapeutic agent.

Animals↗
PubMed1988

Biodistribution of a monoclonal antibody-methotrexate conjugate (791T/36-MTX) in patients with colorectal cancer.

The monoclonal antibody (MAb) 791T/36 which has previously been shown to localise in colorectal cancer has been conjugated to methotrexate (MTX) for potential use as a chemotherapeutic agent in malignant disease. To examine its biodistribution and tumour localisation, 16 patients with primary colorectal cancer were injected intravenously with 131I-labelled 791T/36-MTX conjugate and imaged using a gamma camera after 48-72 hr. Serial blood samples were taken to determine the levels of circulating conjugate and samples of tumour and normal colon were assayed for uptake of radioactivity. Whole body biodistribution, visualised by gamma scintigraphy, and blood clearance of both the antibody and drug moieties of 791T/36-MTX were similar to that previously found with unconjugated antibody. Assays of tissue radioactivity showed positive tumour uptake of drug-antibody conjugate (T:NT greater than 1.9:1) in 13/15 primary tumour specimens (median T:NT = 2.9:1). These studies indicate that 791T/36-MTX conjugates may have potential in the treatment of metastatic colorectal carcinoma.

Aged↗
PubMed1988

Biodistribution and tumour localisation of a daunomycin-monoclonal antibody conjugate in nude mice with human tumour xenografts.

The blood kinetics and tissue distribution of a conjugate of daunomycin and a monoclonal antibody (791T/36) have been examined in mice, including nude mice with human tumour xenografts reactive with the antibody. For this the antibody moiety of the conjugate was labelled with 125I and the drug moiety assayed by radioimmunoassay. After radioiodination, the preparation had an immunoreactive fraction in isotopic binding tests with 791T cells of 74%. Both drug and antibody moieties were precipitable with anti-mouse Ig anti-serum. Following i.v. injection, blood clearance of the two components of the conjugate was essentially identical, and with the serum-borne conjugate both radiolabel and drug were co-precipitable. In mice with 791T xenografts, the tumour showed localisation of both drug and antibody moieties and at the time of analysis (3 days) tumour levels of drug were over 100 times those seen with free drug. In parallel studies with mice with antigen negative xenografts, there was no preferential localisation of antibody or drug moieties of the conjugate. These studies have shown in vivo stability of this conjugate, and site-specific targetting of an anti-tumour anthracycline.

Animals↗
PubMed1988

A rat model for imaging the effect of anti mouse antibody responses on the biodistribution of radiolabelled mouse monoclonal antibodies.

Rats were injected both intradermally and intravenously with an IgG2b mouse monoclonal antibody (791T/36) and subsequently the biodistribution of intravenously injected 111In labelled antibody was examined by gamma camera imaging in these and control rats. The majority of pretreated rats showed a marked perturbation of the biodistribution of the radiolabelled antibody with a marked increase of the tracer in the liver. There was similar perturbation of the biodistribution of subsequently administered 111In labelled Fab fragment of the 791T/36 antibody and of another IgG2b monoclonal antibody. In contrast, there was little influence on the biodistribution of IgG2a or IgG1 monoclonal antibodies, indicating that the response in the rats was predominantly against the IgG2b isotype. This rat model system is amenable to examination of a number of aspects of the biological consequences of immune responses to foreign immunoglobulins relevant to their use for clinical imaging.

Animals↗
PubMed1988

Gamma camera emission tomography using radiolabelled antibodies.

Single photon emission computed tomography (SPECT) of 52 patients injected with 131I and 111In labelled monoclonal antibodies has been undertaken. Patients with tumours within the thorax or lower abdomen were imaged 48-72 h following administration of 80 MBq 131I or 111In labelled monoclonal antibody. Tumour detection from the reconstructed views was compared with that from the planar images. Studies of patients injected with 131I labelled antibodies required long data collection times otherwise image quality was unsatisfactory. Emission tomography using 111In labelled antibodies provided high quality reconstructed images using data collection times acceptable for most patients, and tumour deposits not confidently detected on planar images were clearly visualised in the axial views. These studies demonstrate the potential of radiolabelled antibody emission tomography.

Antibodies, Monoclonal↗
PubMed1988

A comparison of iodine and indium labelled anti CEA intact antibody, F(ab)2 and Fab fragments by imaging tumour xenografts.

An intact anti CEA monoclonal antibody (C198) and its F(ab)2 and Fab fragments have been radiolabelled with 131I and 111In and their biodistributions and tumour imaging capabilities examined in mice with human tumour xenografts. 131I labelled F(ab)2 and Fab fragments showed improved tumour visualization compared with intact antibody, principally because of the more rapid whole body elimination of the radiolabel. Studies using 111In labelled fragments demonstrated that a major proportion (greater than 60%) of the administered radioactivity was retained in the kidneys and this was detrimental to tumour imaging in the mouse xenograft model. The present study emphasizes the importance of selecting the most appropriate combination of antibody preparation and radiolabel, and that the choice of radionuclide is influenced by both its physical and subsequent pharmacological characteristics.

Animals↗
PubMed1988

Iodine-131 and indium-111 labelled avidin and streptavidin for pre-targetted immunoscintigraphy with biotinylated anti-tumour monoclonal antibody.

Studies have been carried out in mice to examine by gamma camera imaging and dissection analysis the biodistribution of 131I- and 111In-labelled avidin and streptavidin. This has included mice with human tumour xenografts pre-targetted with biotinylated anti-tumour monoclonal antibody. Both iodine-labelled avidin and streptavidin were cleared rapidly from the circulation particularly to kidneys, which showed prolonged retention of the tracer. Similar distribution was seen with 111In-labelled preparations, although here tracer also accumulated in the liver. Radiolabelled preparations could form complexes in vitro with a biotinylated monoclonal antibody. This biotinylated antibody, following radioiodine labelling, localized in xenografts of a human osteosarcoma. When xenografted mice were injected with biotinylated antibody followed by 111In-labelled avidin, levels of tracer per gram of tumour tissue were four times higher than those in non-pretreated mice. However, there was still marked liver and kidney uptake of tracer and, since this dominated the images, tumours were not visualized by scintigraphy.

Animals↗
PubMed1988

Drug-monoclonal antibody conjugates for cancer therapy: potentials and limitations.

The development of monoclonal antibodies against antigens associated preferentially with human tumors has reawakened interest in the use of antibodies as site-specific targeting agents for cancer therapy. There are now many reports of the construction of conjugates of drugs and toxins with antibodies which have in vitro toxic properties directed by the antibody moiety. Only recently, however, have limitations to the in vivo therapeutic application of these conjugates become appreciated. These include limited levels of antibodies accumulating in tumor deposits in patients, sometimes marked differences in the biodistribution of antibody-drug conjugates from those seen with free antibody, limited penetration of antibody and drug-antibody conjugates into tumor tissue together with heterogeneity of antigen expression within tumor, and limitation to the cytotoxicity of conjugates caused by the low drug to antibody molar ratios possible without denaturation. It is now becoming appreciated that effective development of this approach will require more than chemical conjugation of existing or even novel drugs or toxins to antibodies so that they are cytotoxic in vitro. Additional strategies will probably have to be employed, including the use of intermediate carriers to increase drug to antibody ratios in conjugates, the production of conjugates without extreme overall charge or conformation changes, techniques to increase antibody localization into tumors by, for example, regional perfusion, blood flow enhancement, or increase in antigenic expression, or the use of conjugates containing mixtures of antibodies or fragments directed against different tumor-associated antigens.

Antibodies, Monoclonal↗
PubMed1988

The implications of patient antibody response for the clinical usefulness of immunoscintigraphy.

The evolving clinical role for tumour immunoscintigraphy appears to be in monitoring patients for metastatic spread and tumour recurrence. Such diagnostic strategies inevitably involve repeat imaging investigations, and therefore the probability of patient immunization against the administered radiopharmaceutical is increased. Patient antibody responses would appear to affect the quality and sensitivity of repeat imaging studies, and this also has implications for the therapeutic efficacy of subsequent therapy doses. A simple test for determining patient sensitization to antibody is required.

Antibodies, Monoclonal↗
PubMed1987

Biodistribution of ricin toxin A chain-monoclonal antibody 791T/36 immunotoxin and influence of hepatic blocking agents.

Immunotoxin constructed by conjugating ricin A chain to monoclonal antibody 791T/36 has a markedly altered biodistribution when compared to unconjugated antibody. This is principally manifest as hepatic uptake of immunotoxin which appears to be controlled by the ricin A chain (RTA) moiety. This was established by comparing the blood survival and organ distribution of immunotoxin with that of ricin A chain and free antibody using preparations in which either the RTA or antibody, alone or as components of the immunotoxin, was radiolabeled. Gel filtration chromatography of sera from immunotoxin treated animals demonstrated a preferential blood clearance of immunotoxin with high RTA-antibody ratio. Hepatic uptake is dependent upon Kupffer cell recognition of mannose-containing oligosaccharide structures on the RTA moiety of immunotoxin. Mannose-containing blocking agents given with immunotoxin were shown to prolong circulation time of the immunotoxin in blood including those species with higher RTA-monoclonal antibody ratios and reduce liver uptake. Effective blocking agents include ovalbumin, ovomucoid, and mannosyl-lysine (Man3Ly2). These studies demonstrate that agents specifically inhibiting hepatic uptake of immunotoxin significantly alter biodistribution and may improve their therapeutic efficacy.

Animals↗
PubMed1987

Inhibition of growth of human tumor xenografts in athymic mice treated with ricin toxin A chain-monoclonal antibody 791T/36 conjugates.

Immunotoxin constructed by conjugating ricin A chain to monoclonal antibody 791T/36 specifically inhibits growth of human tumor xenografts which express the gp72 antigen recognized by the antibody component. Dose schedule tests showed that the major response was obtained during the first 5 days of treatment and further prolonged treatment did not improve therapy. Expression of gp72 antigen on tumor cells derived from xenografts in immunotoxin-treated mice was not markedly altered indicating that treatment did not lead to the expansion of tumor antigen deficient tumor cells. The experiments indicate that treatment for short duration with immunotoxin may be the most effective protocol.

Animals↗