Efficacy and toxicity of anti-CD40 monoclonal antibodies in the treatment of malignancy
Efficacy and toxicity of anti-CD40 monoclonal antibodies in the treatment of malignancy
In recent years, monoclonal antibodies (mAbs) have established themselves as the most rapidly expanding class of therapeutic agents for a wide range of human diseases including cancer. This project has examined the efficacy and toxicity of mAbs directed against the CD40 antigen. CD40 is a type I transmembrane protein belonging to the tumour necrosis factor receptor (TNFR) super-family. It is expressed primarily on antigen presenting cells but is also expressed on a broad range of malignancies. CD154 (CD40L) is the natural ligand for CD40 and is expressed predominantly on activated CD4+ T helper lymphocytes. Normal, bi-directional CD40-CD154 interactions are central to the generation of both T cell dependent, humoral immune responses and cytotoxic T cell responses. Tumour expression of CD40 and the important functional role of CD40-CD165 in-vivo make CD40 an attractive target for antibody based anti-cancer immunotherapy.
I have demonstrated in-vitro that a mouse/human chimeric anti-CD40 mAb developed within the Cancer Sciences Division (Chi Lob 7/4) is able to cause growth inhibition and effectively recruit immunological effector mechanisms such as complement-dependent cytotoxicity (CDD) and antibody directed cellular cytotoxicity (ADCC) against a number of malignant cell lines. I have evaluated the toxicity of anti-CD40 mAb administration in a comparative mouse model and found a reversible hepatitis and splenomegaly to be the principal toxicities of treatment. I have developed and validated an immunohistochemical method for the detection of CD40 expression on normal and malignant human tissue and developed an enzyme linked immunosorbant assay for the quantative detection of serum Chi Lob 7/4.
Substantial funding has been acquired from the New Agents Committee of Cancer Research UK for the development of a phase I clinical trial of Chi Lob 7/4 in the treatment of CD40 positive malignancies refractory to conventional therapy. A preliminary trial protocol has been developed and clinical grade antibody production is underway. It is hoped that the trial will open to recruitment in mid 2004.
University of Southampton
Geldart, Thomas Richard
4a13daf9-2264-4961-b2c5-b4e048359ebf
2004
Geldart, Thomas Richard
4a13daf9-2264-4961-b2c5-b4e048359ebf
Geldart, Thomas Richard
(2004)
Efficacy and toxicity of anti-CD40 monoclonal antibodies in the treatment of malignancy.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
In recent years, monoclonal antibodies (mAbs) have established themselves as the most rapidly expanding class of therapeutic agents for a wide range of human diseases including cancer. This project has examined the efficacy and toxicity of mAbs directed against the CD40 antigen. CD40 is a type I transmembrane protein belonging to the tumour necrosis factor receptor (TNFR) super-family. It is expressed primarily on antigen presenting cells but is also expressed on a broad range of malignancies. CD154 (CD40L) is the natural ligand for CD40 and is expressed predominantly on activated CD4+ T helper lymphocytes. Normal, bi-directional CD40-CD154 interactions are central to the generation of both T cell dependent, humoral immune responses and cytotoxic T cell responses. Tumour expression of CD40 and the important functional role of CD40-CD165 in-vivo make CD40 an attractive target for antibody based anti-cancer immunotherapy.
I have demonstrated in-vitro that a mouse/human chimeric anti-CD40 mAb developed within the Cancer Sciences Division (Chi Lob 7/4) is able to cause growth inhibition and effectively recruit immunological effector mechanisms such as complement-dependent cytotoxicity (CDD) and antibody directed cellular cytotoxicity (ADCC) against a number of malignant cell lines. I have evaluated the toxicity of anti-CD40 mAb administration in a comparative mouse model and found a reversible hepatitis and splenomegaly to be the principal toxicities of treatment. I have developed and validated an immunohistochemical method for the detection of CD40 expression on normal and malignant human tissue and developed an enzyme linked immunosorbant assay for the quantative detection of serum Chi Lob 7/4.
Substantial funding has been acquired from the New Agents Committee of Cancer Research UK for the development of a phase I clinical trial of Chi Lob 7/4 in the treatment of CD40 positive malignancies refractory to conventional therapy. A preliminary trial protocol has been developed and clinical grade antibody production is underway. It is hoped that the trial will open to recruitment in mid 2004.
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Published date: 2004
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Local EPrints ID: 465362
URI: http://eprints.soton.ac.uk/id/eprint/465362
PURE UUID: e7026338-40e8-42a0-b1f7-0aefc1775afc
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Date deposited: 05 Jul 2022 00:40
Last modified: 16 Mar 2024 20:07
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Author:
Thomas Richard Geldart
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