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I Spendlove

Publications and source records attributed to I Spendlove.

14 recordsLinked to original sources
PubMed2003

Enhanced expression of the complement regulatory protein CD55 predicts a poor prognosis in colorectal cancer patients.

This study prospectively correlated the level of expression of CD55 on tumours with 7-year survival in 136 colorectal cancer patients. Patients with tumours expressing high levels of CD55 had a significantly worse survival (24%) than patients with low CD55 levels (50%, p<0.02). A similar difference was seen for patients (Duke's B or C) with a high risk of recurrence (29% vs 58%, p<0.05). Furthermore, there was a progressive deterioration in prognosis with increasing antigen expression ( p=0.01). It remains unclear if CD55 is overexpressed by tumours to protect them from complement or if it is related to the recent observation that CD55 is a ligand for the T-cell activation antigen CD97. However, it is a marker of aggression, as colorectal cancer patients whose tumours overexpress CD55 have a significantly reduced 7-year survival.

Aged↗
PubMed2002

The role of CD55 in protecting the tumour environment from complement attack.

CD55 is a complement regulatory protein expressed by cells to protect them from bystander killing by complement. CD55 is over-expressed 2-100-fold on tumour cells and is deposited in large amounts within tumour matrix. Vascular endothelial growth factor (VEGF) produced by tumours to stimulate angiogenesis, also up-regulates endothelial cell surface expression of CD55 and stimulates the release of matrix degrading metalloproteinases. This study investigated the effects of VEGF on CD55 deposition into matrix and the release of CD55 by metalloproteinases. In contrast to inflammatory cytokines, CD55 was up-regulated by VEGF at the cell surface and within the extracellular matrix (ECM). Interestingly, human umbilical vein endothelial cells (HUVEC) exposed to VEGF released similar amounts of CD55 into the ECM as a tumour cell line expressing 50-fold higher level of CD55 on its cell surface. Furthermore, in contrast to earlier studies, both tumour and HUVEC-derived CD55 was functionally active. However, in contrast to papain that degrades CD55, and collagenase that fails to release CD55, MMP-7 released intact CD55 from ECM. This suggests that it may have a further role to play in protecting cells during inflammation and invasion.

CD55 Antigens↗
PubMed2001

Human anti-idiotypic antibodies can be good immunogens as they target FC receptors on antigen-presenting cells allowing efficient stimulation of both helper and cytotoxic T-cell responses.

Anti-idiotypic antibodies that mimic tumour-associated antigens can stimulate anti-tumour T-cell responses. In this article, we have studied the role of Fc in the presentation of T-cell epitopes by 2 anti-idiotypic antibodies, 105AD7 and 708. The human monoclonal antibody 105AD7, which mimics CD55, stimulated strong in vitro T-cell proliferation, gammaIFN secretion and redirected cytotoxicity in unprimed T cells from healthy donors. However, removal of the Fc region of the anti-idiotype reduced the sensitivity of the assay 1,000-fold, as did inhibiting Fc uptake of the anti-idiotype by an excess of human IgG. The mouse anti-idiotype 708, which mimics CEA, failed to stimulate in vitro T-cell responses on unprimed T cells from healthy donors. However, when a human IgG1 Fc region replaced its mouse Fc region, the anti-idiotype induced T-cell proliferation, gammaIFN secretion and redirected cytotoxicity in lymphocytes from unimmunised donors. Human anti-idiotypes are therefore good immunogens since they target Fc receptors on antigen-presenting cells, allowing efficient stimulation of both helper and cytotoxic T-cell responses. The immunogenicity of other anti-idiotypes may therefore be enhanced by human Fc targeting of antigen-presenting cells.

Animals↗
PubMed2001

CD55 is over-expressed in the tumour environment.

CD55 is a protein that protects cells from complement-mediated attack. 791Tgp72 is an antigen which has been used successfully as a target for both tumour imaging and cancer vaccines. 791Tgp72 has recently been identified as CD55. Quantitative expression of CD55 in the tumour environment was therefore studied. Tumour cells showed a 4-100-fold increase in CD55 cell surface expression when compared to normal cells. Immunohistochemical staining of colorectal tumours also revealed high expression of CD55 in the stroma. To examine the source of this stromal CD55 the ability of both epithelial cells and endothelial cells to produce extracellular CD55 was measured. Tumour cell lines deposit CD55 into their extracellular matrix (ECM) in direct proportion to their cell surface expression. In contrast the ECM from HUVEC cells contained large amounts of CD55 despite expressing low levels of CD55 on their cell surface. Furthermore expression of CD55 on HUVEC cells was increased by exposure to VEGF. Although it remains unclear why CD55 is upregulated in the tumour environment its high level of expression on tumour cells and associated endothelium may explain why it is a good target for both imaging and immunotherapy.

Antigens, Neoplasm↗
PubMed2001

Immunization against tumor cell surface complement-regulatory proteins.

Complement is an enzymatic cascade that results in the release of pro-inflammatory anaphylatoxins, C3b deposition and the assembly of the membrane attack complex (MAC), which results in cell lysis. Cells express complement regulatory proteins or inhibitors to protect themselves from bystander attack by complement. Expression of the complement-regulatory proteins CD55, CD46 and CD59 are deregulated in cancer with tumors showing loss of one or more inhibitors and strong overexpression of others. This results in tumors that are resistant to attack by complement and is a major limitation in the use of monoclonal antibodies as monotherapies. However, tumor sensitivity to complement can be restored by co-administration of antibodies that bind to the functional domains of complement-regulatory proteins. Overexpression of complement-regulatory proteins on tumors also makes them potential targets for cancer vaccines. However, these vaccines have to be carefully designed to induce immune responses that recognize inhibitors overexpressed on tumors and that do not detect the levels expressed by normal cells. A human anti-idiotypic antibody that mimics CD55 has been used successfully in over 200 colorectal cancer and osteosarcoma patients. 70% Of patients show CD55-specific immune responses with no associated toxicity. Similar vaccines targeting CD46 and CD59 would eliminate any cell overexpressing a complement inhibitor. Any remaining tumor cell or any tumor cell that loses complement-regulatory proteins in response to therapy would become highly susceptible to in situ complement deposition. In summary, targeting complement-regulatory proteins is a very attractive approach to tumor therapy, although great care must be taken in preventing normal tissue recognition as this could lead to uncontrolled complement deposition and massive cell lysis.

Animals↗
PubMed2000

105Ad7 cancer vaccine stimulates anti-tumour helper and cytotoxic T-cell responses in colorectal cancer patients but repeated immunisations are required to maintain these responses.

105AD7 is a human anti-idiotypic antibody that recognises the binding site of the anti-tumour antibody 791T/36 and can thereby mimic the CD55 antigen. The molecular basis of 105AD7 mimicry has been identified with 3 CDR regions of 105AD7 showing similarity to 3 regions of CD55. These regions have been analysed for potential T-cell epitopes, and sequences that are predicted to bind to HLA/A1, 3,24 and to HLA/DR1,3,7 have been identified within the CDRH3 region of 105AD7. These epitopes should be stimulating CD8 and CD4 responses, respectively. This prediction was tested on 12 colorectal cancer patients receiving 105AD7 therapy. There was good concordance in 10 of 11 patients between accumulation of CD8RO cells or tumour killing and expression of HLA/A1,3,24. The only patient who failed to respond had a non-permissive class II haplotype and failed to show a helper response. Again 10 of 11 patients showing accumulation of CD4RO cells, in vitro blastogenesis responses, enhanced IL-2 or enhanced NK activity expressed one or more of the HLA/DR1,3,7 haplotypes. Although there was a consistent accumulation of CD45RO cells following 14 of 18 immunisations, only one patient showed a sustained memory response. Our results suggest that 105AD7 can stimulate CD4 and CD8 responses in patients with the appropriate haplotype. However, it may be necessary to continue to immunise, since few patients produce a sustained memory response.

Antibodies, Anti-Idiotypic↗
PubMed2000

Characterisation of a mouse monoclonal anti-idiotype reactive with a V region sequence commonly used by human immunoglobulins.

BACKGROUND: A mouse monoclonal antibody (2C7/IgG2b kappa) has been described recently, which is directed against the major house dust mite allergen Der p 1, and whose epitope specificity is representative of a major component of the human IgE anti-Der p 1 response. AIMS: To characterise an anti-idiotypic antibody (2G10/IgG1 kappa) raised against monoclonal antibody 2C7 as surrogate human IgE anti-Der p 1. METHODS: The specificity of the anti-idiotype antibody 2G10 was determined by competitive inhibition experiments using human and mouse immunoglobulins of known VH gene families. The epitope recognised by monoclonal antibody 2G10 was located on the molecular model of the Fv (fragment variable) region of monoclonal antibody 2C7. RESULTS: The data suggest that monoclonal antibody 2G10 is directed against a crossreactive idiotype on human IgE that is shared by polyclonal IgG. Competitive inhibition studies against human immunoglobulins, representative of VH2, VH3, and VH4 gene families, showed that monoclonal antibody 2G10 is mostly likely to be directed against sequences encoded by either VH3 or VH4 genes. The fact that monoclonal antibody 2G10 binds to the humanized (complementarity determining region (CDR) grafted) CAMPATH-1H antibody, but not to the original rat CAMPATH-1 YTH34.5.6 antibody, indicates that it is directed against a framework region rather than the CDRs. Analysis of amino acids in the VH region for charge, hydrophobicity, and accessibility suggests that reactivity with monoclonal antibody 2G10 is defined by a hexapeptide spanning residues 74-79 within framework region 3. CONCLUSION: The anti-idiotype monoclonal antibody 2G10 could potentially be used as a probe for determining the contribution of the VH3 and VH4 gene segments to antigenic specificity.

Amino Acid Sequence↗
PubMed1999

Decay accelerating factor (CD55): a target for cancer vaccines?

The 791Tgp72 antigen has been used successfully as a target for tumor imaging and T-cell immunotherapy. We have characterized this antigen using the monoclonal antibody 791T/36 as a 72/66 kDa doublet. NH2-terminal protein sequencing of the two bands revealed identity with the complement regulatory protein CD55. Antibodies recognizing different domains of CD55 were also shown to bind to the purified 791Tgp72, although sequence analysis of the cDNA cloned from 791T tumor cells showed 100% homology with CD55 and transfection of the cDNA into antigen-negative CHO cells resulted in binding of 791T/36. This identifies the tumor antigen 791Tgp72 as CD55. This protein protects cells from complement attack; however, it can also transduce signals in lymphocytes and is a ligand for CD97, expressed by activated T cells. These results suggest that CD55 plays a role in signaling between the innate and adaptive immune responses. It is therefore a very intriguing target, because absence of the molecule makes the tumor cells susceptible to complement, whereas protective overexpression results in the antigen being a target for T-cell immunotherapy.

Amino Acid Sequence↗
PubMed1997

Low doses of 105AD7 cancer vaccine preferentially stimulate anti-tumor T-cell immunity.

Clinical studies with the human anti-idiotypic antibody 105AD7 have clearly shown that 791Tgp72 is a good target antigen for cell-mediated immunity. No antibody-related toxicity was observed in any of the 135 patients entered into phase I/II clinical trials of 105AD7, whereas both helper and cytotoxic T-cell responses were induced. The helper responses were exemplified by induction of interleukin-2 (IL-2), antigen-specific blastogenesis, and enhanced natural killer (NK) activity. Anti-tumor cytotoxicity was measured directly and was supported by activation of circulating CD8 cells. In this study, it is shown that a 100-microgram injection of 105AD7 was more effective than the 200-microgram dose. Enhanced IL-2 production was observed following 15/19 injections of 100 micrograms of 105AD7 whereas only 4/11 injections of 200 micrograms of 105AD7 induced responses (p < 0.02). Similarly, time to progression was significantly (p < 0.05) slower (median 6 m) in patients injected with 100 micrograms than patients receiving the higher dose, suggesting that 100 micrograms or lower may be the optimal dose. The standard dose for hepatitis vaccination is 10 micrograms. In vitro blastogenesis assays on naive donors have shown that a dose of 105AD7, which is either too high or too low, fails to activate T cells. The optimal dose in vitro is 10 ng.

Adult↗
PubMed1996

Cancer vaccines.

Explore the source record for details and available documents.

Antibodies, Anti-Idiotypic↗
PubMed1992

alpha B crystallin expression in non-lenticular tissues and selective presence in ubiquitinated inclusion bodies in human disease.

alpha B crystallin is a lens protein which has homology with the small heat-shock proteins and is also expressed in non-lenticular tissues. Polyclonal antibodies have been raised to a synthetic peptide corresponding to residues 1-10 of alpha B crystallin. The antiserum detects a 20 kDa polypeptide on nitrocellulose replicas after polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate of extracts of heart muscle known to be rich in alpha B crystallin. Staining of normal human tissues reveals immunoreactivity of lens capsular epithelium, skeletal muscle, cardiac muscle, smooth muscle, renal tubular epithelium, Schwann cells, and glial cells, as has been described by other workers. In addition, positive staining of normal thyroid epithelium, colonic epithelium, and stratified squamous epithelium was seen. Tissues known to contain ubiquitinated inclusion bodies were immunostained with the anti-alpha B-crystallin antiserum. Staining of cortical Lewy bodies, astrocytic Rosenthal fibres, and hepatic Mallory bodies was seen, but only a proportion of inclusions were positive. Neurones containing the ubiquitinated inclusions of Alzheimer's disease were only very rarely immunostained and the ubiquitinated inclusions of motor neurone disease were not detected by the antiserum. Reactive astrocytes in cerebral tissues were strongly immunostained. The results suggest that alpha B crystallin is involved in the formation of ubiquitinated inclusion bodies that have associated intermediate filaments and support previous observations on the localization of a brain-specific ubiquitin carboxy-terminal hydrolase which similarly divides ubiquitinated filamentous inclusions in the central nervous system into two main groups.

Alzheimer Disease↗
PubMed1992

Production and characterization of a polyclonal antibody to the c-erbB-3 protein: examination of c-erbB-3 protein expression in adenocarcinomas.

A polyclonal rabbit antibody was raised to the c-erbB-3 protein using a synthetic peptide corresponding to amino acids 1229-1241 of the predicted protein sequence of c-erbB-3. In Western blot analysis this antibody detects a single band at approximately 165 kD in a c-erbB-3 transfected (293/HER-3) human cell line. c-erbB-3 protein expression was then examined in a variety of adenocarcinomas. Expression of c-erbB-3 protein was indicated by membrane and/or cytoplasmic tumour cell immunoreactivity in formalin-fixed, paraffin-embedded tissue sections. c-erbB-3 protein was detected in a series of 13 out of 14 primary breast carcinomas, 3 of 5 gastric adenocarcinomas, 8 of 9 colonic adenocarcinomas, 2 of 9 prostatic adenocarcinomas, 0 of 6 renal cell carcinomas, 1 of 4 primary lung adenocarcinomas, and 5 of 7 endometrial adenocarcinomas. Immunohistochemical expression of the c-erbB-3 protein appears to be a relatively common event in adenocarcinomas, and further studies are now warranted to establish the role of the c-erbB-3 protein in neoplasia.

Adenocarcinoma↗
PubMed1992

Ballooned neurons in several neurodegenerative diseases and stroke contain alpha B crystallin.

alpha B crystallin is a protein which has homology with the small cell stress proteins. A characterized antibody to residues 1-10 of alpha B crystallin was used to immunostain tissues containing ballooned (chromatolytic, achromasic) neurons. The tissues included two cases of classical Pick's disease, one case of dementia with swollen achromasic neurons in the cortex, two cases of Alzheimer's disease with large numbers of ballooned neurons, two cases of motor neuron disease, four cases of cortico-basal degeneration, and four cases with areas of brain showing swollen neurons adjacent to recent cerebral infarcts. The anti-alpha B crystallin showed strong diffuse cytoplasmic immunoreactivity of swollen cortical neurons in all the diseases. Astrocytes and oligodendroglial cells were also stained in normal tissues as previously described. Weak diffuse immunoreactivity with an antibody to ubiquitin-conjugates was also seen in the swollen neurons from cases of neurodegenerative disease but not following infarction. Ballooned neurons have been shown to contain phosphorylated neurofilament epitopes not normally present in the perikaryonal region. The presence of alpha B crystallin in ballooned neurons, together with previous data which also indicate its close association with intermediate filaments, suggest that alpha B crystallin may be involved in aggregation and remodelling of neurofilaments in disease. The presence of alpha B crystallin in neurons at the edge of areas of cerebral infarction is likely to reflect cells which are regenerating following damage; its detection may therefore be a marker for such cells. On a practical level, the antibody greatly facilitates the localization of such abnormal neurons in diagnostic histology.

Alzheimer Disease↗