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Biomedical subjects

S M Andrew

Publications and source records attributed to S M Andrew.

52 records · Page 3Linked to original sources
PubMed1991

Human T-lymphocytes targeted against an established human ovarian carcinoma with a bispecific F(ab')2 antibody prolong host survival in a murine xenograft model.

A bispecific F(ab')2 fragment with anti-CD3 and antitumor specificity was used to target activated human peripheral blood lymphocytes (PBL) against OVCAR-3 human ovarian carcinoma cells growing i.p. in athymic mice. Mice were given injections of OVCAR-3 cells on day 0 and treated with i.p. injections of activated PBL coated with the [anti-CD3 (TR66) x antitumor (MOv18)] bispecific F(ab')2 on day 4, using an approximate effector:target ratio of 1:1. Treatment was evaluated for the ability either to block tumor growth at 15 days or to prolong survival of tumor-bearing mice. After 15 days, the incidence of mice with tumor growth was 20% among those given PBL coated with bispecific F(ab')2, whereas the incidence among mice untreated or treated with PBL alone or PBL with either parental antibody ranged from 80 to 94%. The mean survival time of tumor-bearing mice treated with PBL and bispecific F(ab')2 was 104 days, which was 3.5 times that of untreated mice and twice that of mice given PBL alone or PBL with either parental antibody. These results provide support for the concept that treatment of ovarian cancer patients with targeted T-cells could prove beneficial.

Animals↗
PubMed1991

Human peripheral blood lymphocytes targeted with bispecific antibodies release cytokines that are essential for inhibiting tumor growth.

We have compared the mechanisms by which human PBL targeted with bispecific antibodies either lyse tumor cells or block their growth in culture or in mice. We found that resting PBL were unable to mediate lysis, but were able to block tumor growth. Moreover, targeted PBL were unable to lyse bystander cells, whereas targeted PBL did block the growth of bystander tumor cells in culture and in nude mice. Supernatants from cultures of targeted PBL, or from PBL grown on anti-CD3-coated flasks, blocked the growth of tumor cells in the absence of added effector cells, and antibodies against TNF-alpha and IFN-gamma reversed the inhibition of tumor growth, but had no effect upon cytolysis mediated by targeted by PBL. Our results show that targeted human PBL mediate two different antitumor activities: lysis, which occurs rapidly and requires the direct attachment of the target cell to the cytotoxic cell, and tumor growth inhibition, which is mediated by cytokines released into the medium as a result of receptor cross-linking. The inhibition of bystander tumor growth in mice by targeted PBL suggests that factor release is sufficient to block tumor growth in vivo. Targeted factor release therefore provides a mechanism by which targeted PBL could block the growth of tumor cells in vivo that were not bound by the effector cells, but which were located in the vicinity of tumor cells that were bound.

Animals↗
PubMed1991

An investigation into the role of inflammatory cells in Dupuytren's disease.

An immunohistochemical study was performed on nodules excised from the palmar fascia of patients with Dupuytren's contracture. In cellular nodules, antibodies to actin (used as a marker for myofibroblasts), desmin, vimentin, Mac 387 (a macrophage marker) and leucocyte common antigen were used. A correlation was demonstrated between the numbers of macrophages and the presence of myofibroblasts. The presence of myofibroblasts is generally considered to indicate the active stage of the disease. Inflammatory cells other than macrophages were largely absent from the nodules, although lymphocytes were frequent in the tissue around the nodules. Microvascular changes were prominent in the nodules and pericyte proliferation was observed around occluded capillaries. Release of growth factors from macrophages may be important in Dupuytren's contracture, as is the case in other fibrotic diseases. The possible role of macrophages in the aetiology of Dupuytren's disease is discussed.

Dupuytren Contracture↗
PubMed1991

Net energy for lactation of calcium salts of long-chain fatty acids for cows fed silage-based diets.

The NEL of calcium salts of long-chain fatty acids from palm oil was determined in mature Holstein cows. Twelve lactating (fed for ad libitum intake) and six nonlactating (restricted to near maintenance intake) Holstein cows were fed 0 or 2.95% fat supplement in diets formulated to contain 16 or 20% CP in a 2 x 2 factorial arrangement of treatments in a single reversal design within protein level. The fat supplement was substituted for ground corn and minerals. Two 6-d total collection balance trials were conducted during which cows were in open circuit respiration chambers. Intake of OM was lower for lactating cows fed the fat supplement (18.1 vs. 19.1 kg/d), but energy intake did not differ (93.2 Mcal/d). Total long-chain fatty acid intake was increased from 477 to 820 g/d with fat feeding. Apparent digestibility of long-chain fatty acids was increased 11.1 percentage units with increased dietary CP for lactating cows with no difference in fatty acid digestibility for the dry cows. Milk yield was higher (34.3 vs. 32.0 kg/d) with fat feeding, but milk energy yield did not differ (22.6 Mcal/d). The NEL of the fat supplement was estimated from the incremental differences in energy values within cows, assuming NEL of corn replaced by fat to be 1.96 Mcal/kg DM, and was determined to be 6.52 Mcal/kg DM (SE = 1.74). The efficiency of the use of metabolizable energy for lactation from dietary fat was 77.2%. The energy in calcium salts of long-chain fatty acids is utilized efficiently for lactation in mature cows.

Animals↗
PubMed1990

Tumor localization by combinations of monoclonal antibodies in a new human colon carcinoma cell line (LIM1899).

One of the problems of in vivo diagnosis and therapy of tumors with monoclonal antibodies is their heterogeneity with respect to antigen expression, with some cells expressing no antigen and others being weakly or strongly positive. Selected mixtures of antibodies to different antigens are therefore likely to react with more cells than single antibodies and be more effective for imaging and therapy. With this in mind, we have examined a new human colon cancer cell line (LIM1899) which has a heterogeneous expression of several cell surface molecules: by flow cytometry 38% were carcinoembryonic antigen positive; 64%, human milk fat globule positive, and 73%, CD46 positive; 87% of tumor cells bound a mixture of all three antibodies in vitro. Some blocking of the binding of anti-human milk fat globule antibody by the anti-CD46 antibody was noted. LIM1899 was established as a xenograft in nude mice and in vivo biodistribution studies performed using antibodies alone or in combination. Mixtures of antibodies clearly showed a higher percentage of injected dose of antibody in the tumor than did single antibodies: one antibody gave 10%; two together, 17 to 21%; and all three together gave 29% of the injected dose in the tumor. Tumor:blood ratios were also superior for combinations of antibodies, provided that low doses of the antibodies were used; at higher doses the effect was lost. The study demonstrates that combinations of antibodies are better than single antibodies for localization, provided that the dose used is carefully selected.

Animals↗
PubMed1990

Comparison of in vitro cell binding characteristics of four monoclonal antibodies and their individual tumor localization properties in mice.

Although many antibodies are being used for imaging studies, it is not clear which in vitro properties of antibodies will best reflect their in vivo characteristics. The ability to correlate in vitro binding characteristics of monoclonal antibodies to tumor antigens with their in vivo localization characteristics, particularly with respect to tumor localization properties, is desirable for rapid selection of monoclonal antibodies with potential for clinical use. The in vitro binding characteristics of three monoclonal antibodies to the murine Ly-2.1 antigen and one to the Ly-3.1 antigen have been studied on cultured tumor cells bearing these antigens. The association and dissociation rate constants, apparent affinity, and immunoreactivity of each antibody in vitro were compared with their ability to localize the s.c. tumors from the same cell line growing in Ly-2.1-/Ly-3.1-mice. The antibody with the highest affinity and fastest association rate localized to tumor at the earliest time (16-20 h after injection) and had the highest percentage of the injected dose/g in the tumor (greater than 25%). The antibody with the lowest affinity showed significantly less localization to tumor cells, compared with the other three antibodies. The ranking of the antibodies by affinity agreed with the ranking in terms of their ability to localize to tumors, but the in vitro immunoreactivity of the antibodies, as measured by a cell binding assay, did not correlate with their tumor localization properties. Immunoscintigraphic studies did not precisely correlate with biodistribution data or in vitro binding characteristics, because tumors could be satisfactorily imaged with each antibody, although it was noted that the antibody with the highest affinity gave the best image. The results indicate that kinetic binding parameters and affinity of monoclonal antibodies may be useful in predicting their potential for tumor localization and that kinetics of association of antibodies in vitro may predict localization kinetics in vivo.

Animals↗
PubMed1990

Human non-lineage antigen, CD46 (HuLy-m5): purification and partial sequencing demonstrates structural homology with complement-regulating glycoproteins.

CD46, until recently known as HuLy-m5, is a non-lineage restricted surface antigen ubiquitously expressed by almost all human cells except erythrocytes. The CD46 antigen is identified by the E4.3 monoclonal antibody (mAb) and exists at the surface of human peripheral blood lymphocytes (PBLs) as two acidic, non-disulfide bonded chains, alpha and beta, of Mr 66,000 and 56,000. Receptor density analysis showed that CD46 was of moderately low abundance on PBLs with 7.5 x 10(3) molecules present on each cell. The two chains of CD46 were purified (144,000-fold) by immunoaffinity-chromatography with E4.3 mAb from the plasma membranes of a human spleen infiltrated with chronic myelogenous leukemia cells. Amino acid sequence analysis of the NH2-terminal of both alpha and beta chains yielded the same sequence; XEEPPQ/TFEAMELIGKPKPYYEIGE. Peptide mapping studies confirmed that both CD46 chains were closely related, except for one peptide fragment. This amino acid sequence is identical to that of the NH2-terminal of the recently cloned membrane co-factor protein (MCP), a membrane protein that binds the C3b and C4b fragments of complement and acts as a co-factor for I protein-mediated decay of the complement convertases. CD46 shares a cross-reactive epitope with some primate retroviruses, and this may indicate that some retroviruses mimic the mechanisms used by autologous human cells to evade complement-mediated immune clearance.

Amino Acid Sequence↗
PubMed1990

The effect of temperature on the binding kinetics and equilibrium constants of monoclonal antibodies to cell surface antigens.

The effect of temperature on the kinetic association and dissociation binding parameters, and equilibrium constants of four monoclonal antibodies to the murine Ly-2.1 and Ly-3.1 antigens has been studied using flow cytometry. All four monoclonal antibodies were conjugated to FITC and their association to, and dissociation from, the surface of murine thymoma cells was observed at 15 sec intervals, at temperatures between 1 and 37 degrees C. The initial association rate constant and the dissociation rate constant for each antibody at each temperature were calculated from graphs of the first-order reactions and it was demonstrated that an increase in temperature caused an increase in both association rate and dissociation rate of the antibodies. Generally the increase in association rate with temperature was less than the increase in dissociation rate. Differences between antibodies to the same antigen (Ly-2.1) suggest that changes in membrane fluidity were not solely responsible for the changes in association rate. However, the equilibrium constants (Keq) did not always show a simple relationship of increasing temperature causing decreasing values for Keq. For one antibody the highest value for Keq was seen at 17 degrees C rather than at 37 degrees C and differences in Keq between individual antibodies were greater at 1 degree C than at 37 degrees C. Kinetic rate constants are usually measured at 4 degrees C or room temperature, therefore for antibodies under consideration for in vivo use, measurements at 37 degrees C are more appropriate.

Animals↗
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

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↗
PubMed1987

An improved method for the inhibition of endogenous peroxidase non-deleterious to lymphocyte surface markers. Application to immunoperoxidase studies on eosinophil-rich tissue preparations.

The inhibitory effect of phenylhydrazine and azide combined with either pre-formed or nascent hydrogen peroxide H2O2 upon endogenous peroxidatic activity, expressed by tissue eosinophils in different disease states, was investigated. It was found that whilst endogenous peroxidatic activity due to eosinophils in a Hodgkin's disease and a histiocytosis X case were adequately inhibited by phenylhydrazine combines with pre-formed or nascent H2O2, the eosinophils in the Onchocerca volvulus nodule were either not at all or only partly inhibited by the two regimens. On the other hand, a combination of azide with nascent H2O2 proved consistently effective against this resistant form of endogenous peroxidatic activity. Using human tonsil sections this protocol was shown to be non-deleterious to T4('CD4'), T6('CD1') and T8('CD8') lymphocyte surface antigens as evidenced by the application of a standard indirect immunoperoxidase technique and the relevant monoclonal antibodies.

Antigens, Surface↗
PubMed1986

Comparative imaging and biodistribution studies with an anti-CEA monoclonal antibody and its F(ab)2 and Fab fragments in mice with colon carcinoma xenografts.

An IgG1 mouse monoclonal antibody directed against CEA has been digested with papain to yield F(ab)2 and Fab fragments. Following radioiodination, intact antibody and fragments showed specific binding to cells of a CEA-producing tumour, although the immune reactivities of the fragments were lower than that of intact antibody. Gamma scintigraphy of nude mice bearing CEA-producing human tumour xenografts and injected with 131I-labelled fragments showed earlier and superior imaging of tumours than did 131I-intact antibody, and this was most marked with the Fab fragment. Sequential dissection analyses showed that this was due to earlier and higher tumour-to-blood ratios with fragments than with intact antibody, but in absolute terms the degree of localization of both fragment types was significantly lower than that of intact antibody.

Adenocarcinoma↗
PubMed1986

Immunoperoxidase labelled antibody staining in differential diagnosis of central nervous system haemangioblastomas and central nervous system metastases of renal carcinomas.

The problem of the differential diagnosis both of central nervous system haemangioblastomas and metastases of renal clear cell carcinomas was investigated by immunoperoxidase labelled antibody staining of five cases each of haemangioblastoma and metastatic renal carcinoma. Staining using anticarcinoembryonic antigen (CEA), antikeratin, antifactor VIII related antigen, and antibrush border was unhelpful. All five of the haemangioblastomas were negative and all five of the metastases were positive for epithelial membrane antigen (EMA), as defined by immunoperoxidase staining. This shows that commercially available anti-EMA monoclonal antibody is useful in distinguishing the two pathological entities.

Adenocarcinoma↗
PubMedDate not supplied

Properties of monoclonal antibodies to human tumor necrosis factor alpha (TNF alpha).

Four murine monoclonal antibodies were produced against human recombinant tumor necrosis factor alpha (TNF alpha). They were characterized with respect to specificity, affinity, neutralization of in vitro L929 cell killing by TNF alpha and neutralization of the in vivo biological activities of toxicity and tumor necrosis. The monoclonal antibodies were further investigated for reactivity with TNF alpha in Western blotting. All four monoclonal antibodies reacted with human TNF alpha. One of then also reacted with mouse TNF alpha and human TNF beta (lymphotoxin), this antibody did not neutralize in vitro cytotoxicity or in vitro biological activities of TNF alpha. The other antibodies were neutralizing and it appeared that, in some cases, the systemic toxic effect of TNF alpha could be reversed by anti-TNF alpha monoclonal antibody therapy while retaining significant anti-tumour effects.

Animals↗