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Humoral immune responses to XMMCO-791-RTA immunotoxin in colorectal cancer patients
L G Durrant1, V S Byers, P J Scannon
1Cancer Research Campaign Laboratories, University of Nottingham, UK.
Abstract:
Monoclonal antibody 791 (XMMCO-791) recognizes a colorectal tumour-associated antigen. Antibody 791-ricin A chain immunotoxin (XMMCO-791-RTA) inhibits growth of human tumour xenografts and it is therefore being evaluated for the treatment of colorectal cancer. One of the problems with therapy with mouse monoclonal antibodies is they stimulate humoral responses in patients. However antigens linked to ricin are cytotoxic for B cells and therefore XMMCO-791-RTA may not be immunogenic. The humoral antibody response to murine monoclonal antibody XMMCO-791 (IgG2b) conjugated to the plant toxin, ricin A chain (RTA), was measured in colorectal cancer patients in a phase I clinical trial. All patients produced strong responses to the XMMCO-791 immunoglobulin and to RTA. The predominant response to the antibody was against the idiotypic determinant although anti-subclass and anti-mouse antibodies were also detected. A component of the anti-idiotypic immunoglobulin response in the colorectal cancer patients was directed against the combining site of XMMCO-791. These antibodies inhibited in-vitro binding of XMMCO-791 to target 791 cells and so may be inhibitors of repeated immunotoxin therapy. Immunotoxins do not abrogate the immune response to mouse immunoglobulin in vivo but instead are highly immunogenic.
Insights
Colorectal cancer patients receiving the XMMCO-791-RTA immunotoxin developed strong immune responses to both the antibody and the toxin. These responses, particularly anti-idiotypic antibodies, could potentially hinder future treatments.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Monoclonal antibody 791 (XMMCO-791) targets colorectal tumors.
- XMMCO-791 conjugated with ricin A chain (XMMCO-791-RTA) shows potential for colorectal cancer treatment.
- Mouse monoclonal antibodies can elicit immune responses in patients, posing a therapeutic challenge.
Purpose of the Study:
- To investigate the humoral immune response to XMMCO-791-RTA in colorectal cancer patients.
- To determine if XMMCO-791-RTA is immunogenic despite ricin's B cell cytotoxicity.
- To characterize the nature of the antibody response against the immunotoxin.
Main Methods:
- Phase I clinical trial involving colorectal cancer patients.
- Measurement of humoral antibody responses to XMMCO-791 and ricin A chain (RTA).
- Analysis of antibody specificities, including anti-idiotypic, anti-subclass, and anti-mouse responses.
Main Results:
- All patients exhibited strong immune responses to both XMMCO-791 immunoglobulin and RTA.
- Predominant response was anti-idiotypic, with some anti-subclass and anti-mouse antibodies detected.
- A portion of the anti-idiotypic response targeted the XMMCO-791 binding site, inhibiting its in vitro cell binding.
Conclusions:
- XMMCO-791-RTA is immunogenic in colorectal cancer patients.
- The induced anti-idiotypic antibodies may impede repeated immunotoxin therapy by blocking antibody binding.
- Immunotoxins do not prevent but rather enhance immune responses to mouse immunoglobulins.
