Repeated antitumour antibody therapy in man with suppression of the host response by cyclosporin A

Abstract

Summary Antibody targeted therapy of cancer results in anti-antibody production which prevents repeated treatment. Cyclosporin A (CsA) has been used to suppress this response in patients treated with a radiolabelled antibody to carcinoembryonic antigen (CEA). Patients with CEA producing tumours received a minimum of two courses consisting of an injection of radiolabelled antibody and CsA, 24 mg kg-1 day-1, for 6 days; each course was given at 2 week intervals. Two weeks after the completion of the second course the mean human antimouse antibody (HAMA) levels were 3.5 ug ml -1 (s.d. 2.7) in 3 patients receiving CsA and 1,998 pg ml-1 (s.d. 387) in 3 patients not receiving the drug. Clearance of antitumour antibody was accelerated and tumour localisation absent when HAMA levels exceeded 30 pgml-1. With lower levels of HAMA in the CsA-treated patients, further antitumour antibody accumulated in the tumour after each dose. Further therapy with antitumour antibody and CsA lead to the development of HAMA, but this was less than 25% of the amount in patients not given CsA. In this preliminary study up to 4 times as many doses of antitumour antibody could be usefully given when CsA was used. This increases the potential for effective antibody targeted therapy of cancer.Therapy of cancer with intravenous antitumour mouse monoclonal antibodies alone or conjugated to radionuclides or toxins has produced tumour responses but these are seldom sustained (Meeker et al., 1985, Lenhard et al., 1985, Spitler et al., 1987. Repeated therapy would probably be more effective but is prevented by the formation of human antimouse antibody (HAMA) after one or more injections of antitumour antibody (Meeker et al., 1985, Carrasquillo et al., 1984, Shawler et al., 1985. This causes hypersensitivity reactions and prevents antitumour antibody from localising in the tumour.CsA is a powerful inhibitor of humoral immunity (Borel et al., 1976) and has recently been shown in the accompanying paper to prevent the antibody response to repeated injections of mouse monoclonal antibodies in rabbits (Ledermann et al., 1988 The dose of CsA was adjusted to maintain blood levels between 1,000 and 1,500 ng ml -1 and to prevent a progressive rise in serum creatinine levels. Samples for HAMA were measured before therapy and at intervals after each dose. The distribution of radioactivity in the normal tissues and tumour was determined by planar and single photon emission tomography (SPET) imaging using an IGE Gemini gamma camera.HAMA levels were measured by enzyme immunoassay. Dilutions of serum in PBS containing 0.05% Tween and 0.1% bovine serum albumin were incubated for 2h at room temperature in microtitre wells coated with 10 pgml-l A5B7 in carbonate-bicarbonate buffer, pH 9.6. After washing, wells were incubated with goat anti-human IgG conjugated to alkaline phosphatase (Sigma) followed by the addition of pnitrophenyl phosphate. The absorbance was recorded on a Titertek Multiskan. The assay was standardised using HAMA immunopurified on an A5B7-Sepharose-...

Polyethylene glycol modification of a galactosylated streptavidin clearing agent: effects on immunogenicity and clearance of a biotinylated anti-tumour antibody

“…The immunogenicity of murine monoclonal antibodies has been a constant hindrance to antibody-directed therapy of tumours, causing hypersensitivity reactions and also accelerated clearance of the antibody from the circulation, rendering the therapeutic antibody ineffective. The production of antimouse antibodies can be controlled to some extent by immunosuppressive drugs, for example Cyclosporin A (Ledermann et al, 1988), although general immunosuppression of patients is undesirable. To overcome the problem of immunogenicity of murine antibodies, chimeric antibodies constructed from the variable regions of the mouse antibody together with human constant regions have been produced and have shown reduced immunogenicity in man (LoBuglio et al, 1989), as have humanised antibodies constructed from only the hypervariable complementarity-determining regions (CDRs) of the mouse antibody built into the framework of a human antibody (Hale et al, 1988;Hird et al, 1991).…”

Clearance of circulating radio-antibodies using streptavidin or second antibodies in a xenograft model

“…A direct comparison with monoclonal antibodies was not possible, but streptavidin does have the advantage of being applicable to antibodies of different types and to antibody fragments. Both second antibody and streptavidin are likely to be immunogenic in man, but the use of immunosuppressive drugs may overcome this (Ledermann et al (1988).…”

The potential for enhanced tumour localisation by poly(ethylene glycol) modification of anti-CEA antibody

“…Kitamura et al (1991) have shown that PEG attachment to an intact murine monoclonal antibody against human colon cancer reduces the HAMA response significantly when compared with the parent intact antibody. This is very important for RIT, as successful treatment requires repeated doses of antibody and an immune response would significantly reduce the effective radiation dose to the tumour (Ledermann et al, 1988).…”

“…A5B7 is a murine monoclonal anti-CEA antibody (Pedley et al, 1987), which has been used clinically for localisation and therapy trials in our department (Ledermann et al, 1988).…”

“…This is of particular concern in the case of radioimmunotherapy (RIT), multiple doses of which are often required for effective treatment. The result can be both damage to normal tissues from the high circulating levels of radiation and the development of a human anti-mouse antibody response (HAMA), which will lower the therapeutic effect by the formation of rapidly clearing immune complexes, and may also cause anaphylaxis (Ledermann et al, 1988).…”