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Biomedical subjects

G Hale

Publications and source records attributed to G Hale.

At least 19 recordsLinked to original sources
PubMed1992

Humanised monoclonal antibody therapy for rheumatoid arthritis.

Monoclonal antibodies that target T cells have shown some benefit in rheumatoid arthritis although responses have not been long lasting. This is partly due to insufficient therapy consequent upon antibody immunogenicity. Use of humanised antibodies, which are expected to be less foreign to man than conventional rodent antibodies, might overcome this problem. We therefore assessed in a phase 1 open study the potential of a "lymphocyte depleting" regimen of the humanised monoclonal antibody CAMPATH-1H in 8 patients with refractory rheumatoid arthritis. Apart from symptoms associated with first infusions of antibody, adverse effects were negligible. Significant clinical benefit was seen in 7 patients, lasting for eight months in 1. After one course of therapy, there was no measurable antiglobulin response, although 3 out of 4 patients have become sensitised on retreatment. Humanisation reduces the immunogenicity of rodent antibodies but anti-idiotype responses may still be seen on repeated therapy, even in patients sharing immunoglobulin allotype with the humanised antibody.

Adult↗
PubMed1992

Interaction of avidin with the lipoyl domains in the pyruvate dehydrogenase multienzyme complex: three-dimensional location and similarity to biotinyl domains in carboxylases.

Avidin can form intermolecular cross-links between particles of the pyruvate dehydrogenase multienzyme complex from various sources. Avidin does this by binding to lipoic acid-containing regions of the dihydrolipoamide acetyltransferase polypeptide chains that comprise the structural core of the complex. It is inferred that the lipoyl domains of the acetyltransferase chain extend outwards from the interior of the enzyme particle, interdigitating between the subunits of the other two enzymes bound peripherally in the assembled structure, with the lipoyl-lysine residues capable of reaching to within at least 1-2 nm of the outer surface of the enzyme complex (diameter ca. 37 nm). The distribution of enzymic activities between different domains of the dihydrolipoamide acetyltransferase chain implies that considerable movement of the lipoyl domains is a feature of the catalytic activity of the enzyme complex. There is evidence that the lipoyl domain of the 2-oxo acid dehydrogenase complexes is similar in structure to a domain that binds the cofactor biotin, also in amide linkage with a specific lysine residue, in the biotin-dependent class of carboxylases.

Amidohydrolases↗
PubMed1992

In vivo use of Campath-1G to prevent graft-versus-host disease and graft rejection after bone marrow transplantation.

Twenty-two patients (16 male, six female; median age 34 years, range 16-49) with acute myeloid leukemia (1st complete remission (CR), n = 9), acute lymphocytic leukemia (1st CR, n = 5), chronic myeloid leukemia (chronic phase n = 5, accelerated phase n = 1), malignant lymphoma (n = 1) and myeloma (n = 1) were transplanted with unmanipulated donor bone marrow after standard conditioning including the monoclonal antibody Campath-1G daily from day -4 to day 0. No further graft-versus-host disease (GVHD) prophylaxis was given. All patients engrafted and neither graft failure nor rejection were observed. Acute GVHD grade I (skin) was seen in 12 out of 21 patients at risk. Acute GVHD grade II (skin) occurred in two patients. Severe GVHD (grade III, IV) of the gut, liver and skin developed in two patients. The overall incidence of severe acute GVHD (II-IV) was 19% of the patients at risk. Chronic GVHD (skin only) was seen in eight patients (42%) (six of extensive severity). A total of 14 patients died, the causes being relapse (four), direct cytotoxic drug toxicity (one), a GVHD (two), disseminated varicella zoster (one), systemic tuberculosis (one), interstitial pneumonitis (three) and veno-occlusive disease (two). These results indicate that the intravenous administration of Campath-1G may have reduced the incidence of severe acute GVHD without the occurrence of graft failure. However, the incidence of chronic GVHD does not appear to have decreased.

Adolescent↗
PubMed1991

Characterization of the CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide backbone.

The CAMPATH-1 (CDw52) antigen has been purified from human spleen. The antigenic epitope is heat stable but sensitive to mild alkali treatment. Experiments with phosphatidylinositol-specific phospholipase C indicate that it is anchored by a glycosylphosphatidylinositol (GPI) anchor. An N-terminal sequence of 11 amino acids was determined, followed by an abrupt stop. Using short overlapping mixed oligonucleotide primers, cDNA synthesized from the mRNA of a human B cell line was amplified by the polymerase chain reaction. The product was used to isolate cDNA clones and the full amino acid sequence of the CAMPATH-1 antigen was deduced. It consists of 37 amino acid residues plus a 24-residue signal peptide. It has all the features expected for a GPI-anchored membrane protein except that the predicted mature protein is remarkably short, comprising no more than 18 residues and possibly as few as 12 (depending on the GPI linkage site). Potential attachment sites for carbohydrate are present and it is shown that the antigen contains N-linked oligosaccharide(s). This structure accounts for the known properties of the antigen, though the exact reasons why it is such a good target for cell lysis in vitro and in vivo are not yet clear.

Amino Acid Sequence↗
PubMed1991

Humanized monoclonal antibody treatment in rheumatoid arthritis.

A 41-year-old woman with active, seropositive erosive rheumatoid arthritis was treated with the humanized monoclonal antibody Campath 1H. She had not responded or developed side effects to myocrisin, sulfasalazine and penicillamine, and had not responded to inpatient bedrest and physiotherapy. There was a rapid clinical improvement within 24 hours of infusion, which was maintained for about 12-14 weeks after the infusion. The lymphocyte count was suppressed for 7 months after treatment. There were no significant side effects during or after treatment. No anti-Campath 1H response was detected. This preliminary study suggests humanized monoclonal antibody therapy may be of value in the treatment of rheumatoid arthritis.

Activities of Daily Living↗
PubMed1990

Complement activation by immunoglobulin does not depend solely on C1q binding.

A matched set of rat chimeric antibodies has been studied for their ability to activate various key stages of the complement cascade. Rat IgM and IgG2b were efficient at all stages from C1q binding to cell lysis. However, for other isotypes, a direct correlation between C1q binding and cell lysis did not apply. IgG2a, which was only modestly efficient at C1q binding, was relatively more so for binding and activation of while C1, and was by far the most effective isotype after IgG2b and IgM for C4 and C3 binding. IgG2c was relatively efficient at binding C1q and C1, but less so for the binding of C4 or for later stages. IgA was efficient at binding C1, but again, this was not reflected in activation of later stages. The results suggest that properties of different isotypes, as well as influencing binding of C1q, may regulate attachment of the C1r2C1s2 tetramer. In addition, distinct features of certain isotypes may favor C4 activation and binding, independent of their ability to activate C1.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1990

"Pacecare"--a computerized database for pacemaker follow-up.

A computerized database for pacemaker follow-up has been designed to run on IBM compatible hardware and to accept pulse generator and lead models of all manufacturers. Stored data includes patient, physician and implant details, indications for pacing, underlying rhythm, complications and management, program settings, and follow-up measurements. Typing is minimized by the use of "pop-up" lists and prepared pulse generator template displays. At each follow-up visit a patient's file is retrieved by surname or number, a visit record created, and measurements documented. As the template of the previous visit is used, recording of the clinic visit takes less than 1 minute. Changes in pacing rates (base or magnet), pulse widths, lead thresholds, lead impedance, and battery cell impedance can be displayed graphically for immediate recognition of end-of-life parameters or suspected malfunction. The program will print patient, implantation and clinic visit summary reports, clinic appointment lists, letters to patients, and annual reports. Two Melbourne hospitals have now entered over 3,600 patients into the database. Valuable information has been obtained regarding implantation details and trends with pulse generator and lead usage. Pacecare is a sophisticated, yet user friendly, computerized database for pacemaker follow-up. Recording of clinic visits is fast and changes in testing parameters can be recognized immediately.

Computer Systems↗
PubMed1990

Purging in auto- and allografts: monoclonal antibodies which use human complement and other natural effector mechanisms.

CAMPATH-1M is a rat IgM monoclonal antibody which binds to an antigen on all human lymphocytes and monocytes, but which is not present on marrow stem cells (Hale et al., 1983). Lymphocytes can be efficiently killed in bone marrow buffy coat preparations using the antibody and donor human serum as a means to avoid graft versus host disease (GVHD) (Waldmann et al., 1984). An analysis of 520 matched sibling bone marrow transplants (BMT) for leukaemia demonstrates that T-cell depletion using CAMPATH-1M markedly reduces the incidence and severity of GVHD, but there is an increased risk of graft rejection. In the case of CGL in chronic phase, there is also an associated extra risk of relapse, particularly in patients where engraftment may have been compromised (Hale et al., 1988a). A rat IgG2b antibody of the same specificity as CAMPATH-1 (CAMPATH-1G) was developed which is able to both fix human complement and opsonize lymphocytes in vivo (Dyer et al., 1989). Initial studies for the prophylaxis of bone marrow rejection in 55 mismatched and matched unrelated donor (MUD) BMTs suggest that CAMPATH-1G treatment of the recipient may reduce, but not eliminate, marrow graft rejection. The broad CAMPATH-1 specificity means that it is also ideal for purging a range of lymphoid malignancies prior to autologous BMT, or even for direct serotherapy of leukaemic patients. However, there may be limitations of monoclonal antibody purging using complement or other natural effector mechanisms either in vivo or in vitro; in particular, antigenic modulation and an antiglobulin response. Phase 1 studies of "in vivo purging" with a monovalent CD3 antibody (Clark et al., 1989), and also with a genetically engineered humanized IgG1 (CAMPATH-1H) (Hale et al., 1988b) suggest that these limitations can be overcome.

Antibodies, Monoclonal↗
PubMed1989

Effect of graft perfusion with two CD45 monoclonal antibodies on incidence of kidney allograft rejection.

In a blind trial, 77 patients were randomised to receive first cadaver kidney allografts that had been perfused either with a pair of CD45 monoclonal antibodies (mAbs), in an attempt to reduce the immunogenicity of passenger leucocytes, or with control human albumin solution. No complications of mAb perfusion were observed. Patient and allograft survival were similar in both groups. Rejection episodes were recorded in 7 (18%) of the patient with mAb perfused allografts compared with 24 (63%) of the controls.

Animals↗
PubMed1989

CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells.

A novel cell surface antigen has been identified on a wide range of lymphoid cells and erythrocytes. A mAb YTH 53.1 (CD59) against this antigen enhanced the lysis of human red cells and lymphocytes by homologous complement. Studies of reactive lysis using different species of C56, and of whole serum used as a source of C7-9, indicated that the inhibitory activity of the CD59 antigen is directed towards the homologous membrane attack complex. CD59 antigen was purified from human urine and erythrocyte stroma by affinity chromatography using the mAb YTH 53.1 immobilized on Sepharose, and, following transient expression of a human T cell cDNA library in COS cells, the corresponding cDNA also identified using the antibody. It was found that the CD59 antigen is a small protein (approximately 20 kD as judged by SDS-PAGE, 11.5 kD predicted from the isolated cDNA) sometimes associated with larger components (45 and 80 kD) in urine. The sequence of CD59 antigen is unlike that of other complement components or regulatory proteins, but shows 26% identity with that of the murine LY-6 antigen. CD59 antigen was released from the surface of transfected COS cells by phosphatidylinositol-specific phospholipase C, demonstrating that it is attached to the cell membrane by means of a glycolipid anchor; it is therefore likely to be absent from the surface of affected erythrocytes in the disease paroxysmal nocturnal hemoglobinuria.

Antibodies, Monoclonal↗
PubMed1989

Effects of CAMPATH-1 antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype.

The CAMPATH-1 family of antibodies recognize an abundant glycoprotein expressed on virtually all human lymphocytes. All rat IgM and IgG antibodies of this specificity are lytic with human complement, but only IgG2b is active in antibody-dependent cell-mediated cytotoxicity (ADCC). We compared the ability of IgM, IgG2a, and IgG2b to deplete lymphocytes in vivo in two patients with prolymphocytic transformation of B-cell chronic lymphocytic leukemia (CLL). The IgM (CAMPATH-1M) produced transient depletion of blood lymphocytes with consumption of complement but had no effect on solid masses or bone marrow. Similar transient depletion of blood lymphocytes was noted with the IgG2a (YTH34.5). In contrast, the IgG2b (CAMPATH-1G) produced long-lasting depletion of lymphocytes from blood and marrow and improvement in splenomegaly but no detectable changes in complement levels. These differences probably reflect the importance of Fc receptor binding for effective clearance of target cells in vivo. We treated 16 more patients with a variety of lymphoid malignancies and noted consistent effects on blood lymphocytes, marrow infiltration, and splenomegaly. At this dose level, there was comparatively little improvement in affected lymph nodes or extranodal masses. Nevertheless, the in vivo lympholytic ability of CAMPATH-1G is very potent as compared with other monoclonal antibodies (MoAbs) and may have applications in therapy of lymphoid malignancies and as an immunosuppressive agent.

Aged↗
PubMed1989

The improved lytic function and in vivo efficacy of monovalent monoclonal CD3 antibodies.

A series of hybrid-hybridomas were derived by the cell fusion of a CD3 antibody-secreting hybridoma with other Ig-producing cell lines. The Ig molecules secreted by these hybrid-hybridomas were fractionated by ion-exchange chromatography, and fractions containing monovalent CD3 antibodies were tested for complement-mediated lysis of T cells. Two monovalent CD3 antibodies with mixed heavy chain isotypes were very poor in lysis but, in contrast, a monovalent antibody possessing two identical rat gamma 2b heavy chains but two non-identical light chains was found to be more lytic with human complement than the parental bivalent CD3 antibody. The difference in lysis was not readily explicable in terms of a difference in complement activation at the level of C1q binding or cell-associated C3. A highly purified batch of this lytic monovalent CD3 antibody was prepared in a form suitable for in vivo therapy. In a preliminary clinical study in one patient with a T lymphoma in leukemic phase this monovalent CD3 antibody was found to be very effective in depleting CD3+ tumor cells in the peripheral blood and bone marrow. The cells in the peripheral blood were completely cleared and there was no evidence for antigenic modulation. In addition the antibody was able to reverse cell-mediated kidney rejection in three kidney graft patients. These results suggest that monovalent antibody may be effective in vivo as well as in vitro and that a fuller clinical evaluation is justified.

Adolescent↗
PubMed1989

Campath-1M--prophylactic use after kidney transplantation. A randomized controlled clinical trial.

Campath-1M is a rat monoclonal IgM antibody that binds human complement and recognizes virtually all peripheral human mononuclear cells. It is known to be effective in T cell depletion of bone marrow grafts, and encouraging results were obtained in a pilot study in which the antibody was used in prevention and treatment of rejection of kidney, pancreas, and liver allografts. In this randomized controlled clinical trial, Campath-1M has been evaluated as a prophylactic agent following renal allografting. It is shown that patients who received a 10-day course of the antibody immediately postoperatively, in addition to standard therapy with high-dose cyclosporine (17 mg/kg), experienced a significantly lower incidence of early acute cellular rejection than control patients who received cyclosporine alone. There was no evidence of "rebound" rejection following the end of antibody treatment to suggest that rejection had merely been delayed. However, patients who received this additional immunosuppression experienced a significantly higher incidence of serious infections than controls, this negating any benefit from the treatment in terms of graft survival. Thus, a monoclonal antibody of broad specificity directed against lymphocytes may be effective as a prophylactic agent after organ transplantation but its use should be accompanied by a reduction in other immunosuppressive drugs.

Antibodies, Monoclonal↗
PubMed1988

Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-1H.

A genetically reshaped human IgG1 monoclonal antibody (CAMPATH-1H) was used to treat two patients with non-Hodgkin lymphoma. Doses of 1-20 mg daily were given intravenously for up to 43 days. In both patients lymphoma cells were cleared from the blood and bone marrow and splenomegaly resolved. One patient had lymphadenopathy which also resolved. These effects were achieved without myelosuppression, and normal haemopoeisis was restored during the course of treatment, partially in one patient and completely in the other. No antiglobulin response was detected in either patient. CAMPATH-1H is a potent lympholytic antibody which might have an important use in the treatment of lymphoproliferative disorders and additionally as an immunosuppressive agent.

Aged↗