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CEA Antibodies

Overview: 

Clinical Phase I. MFE-23 is a single chain Fv antibody that has high affinity for the tumour specific antigen CEA. Successful preclinical and clinical studies support its potential for use in targeted cancer therapies and as an imaging agent. These include Phase I studies of radiolabelled MFE-23 for use as an imaging agent, for radioimmunoguided surgery and as the tumour-targeting moiety of an antibody directed enzyme prodrug therapy. A Phase I study of autologous T cell therapy is in progress. Humanised MFE-23 and higher affinity variants are also available.

The Opportunity: 

Clinical Phase I CEA is a 180 kDa tumour-associated antigen expressed in the developing foetus and a wide variety of tumours, including those of the GI tract (e.g. colon, rectum, pancreas, liver), breast, lung and prostate.

A high-affinity anti-CEA single chain Fv (scFv), MFE-23, has been developed by phage display technology (1). MFE-23 has exceptional specificity for CEA and appears to have no nonspecific reactivity with human tissues. Furthermore, preclinical and clinical studies indicate that MFE-23 localisation to CEA-expressing tumours is not affected by CEA protein being shed into the circulation. A humanised MFE-23 variant (hMFE) has been engineered by using a resurfacing technique and higher-affinity hMFE variants (improved off-rates) generated by mutagenesis and screening yeast surface-displayed libraries. One of these variants, sm3E, has a dissociation halftime of several days and retains approximately 80% anti-CEA binding activity after incubation for 9 days under physiological conditions (37oC). MFE antibodies have been successfully radiolabelled with 123Iodine, 125Iodine, 131Iodine and 99mTc. Economical methods of producing recombinant MFE antibodies and MFE fusion proteins to clinical grade have been developed comprising expression in bacteria or pichia pastoris and purification by immobilised metal affinity chromatography (IMAC) by virtue of an engineered hexahistidine tag.

Extensive preclinical and clinical studies of the Inventors and others indicate that these antibodies are potentially useful imaging agents and have considerable therapeutic potential when linked to a suitable moiety.

The Technology: 

CEA is a 180 kDa tumour-associated antigen expressed in the developing foetus and a wide variety of tumours, including those of the GI tract (e.g. colon, rectum, pancreas, liver), breast, lung and prostate.

A high-affinity anti-CEA single chain Fv (scFv), MFE-23, has been developed by phage display technology [1]. MFE-23 has exceptional specificity for CEA and appears to have no nonspecific reactivity with human tissues. Furthermore, preclinical and clinical studies indicate that MFE-23 localisation to CEA-expressing tumours is not affected by CEA protein being shed into the circulation. A humanised MFE-23 variant (hMFE) has been engineered by using a resurfacing technique and higher-affinity hMFE variants (improved off-rates) generated by mutagenesis and screening yeast-surface-displayed libraries [2]. One of these variants, sm3E (also available in whole IgG format), has a dissociation half-time of several days and retains approximately 80% anti-CEA binding activity after incubation for 9 days under physiological conditions (37oC) [2]. MFE antibodies have been successfully radiolabelled with 123Iodine, 125Iodine, 131Iodine and 99mTc. Economical methods of producing recombinant MFE antibodies and MFE fusion proteins to clinical grade have been developed
comprising expression in bacteria [3] or pichia pastoris [4] and purification by immobilised metal affinity chromatography (IMAC) by virtue of an engineered hexahistidine tag.

Extensive preclinical and clinical studies of the Inventors and others indicate that these antibodies are potentially useful imaging agents and have considerable therapeutic potential when linked to a suitable moiety.

Researchers: 

Professor Richard Begent and Dr Kerry Chester, (University College London), Professor Robert Hawkins (currently at University of Manchester), Professor Dane Wittrup and Christilyn Graff (Massacheusetts Institute of Technology).

References: 

1. Chester KA et al. 1994. Lancet. 343(8895):455-6
2. Graff CP et al. 2004. Protein Eng. Des. Sel. 17(4):293-304
3. Mayer A et al. 2000. Clin. Cancer Res. 6(5):1711-9
4. Sharma SK et al. 2005. Clin. Cancer Res. 11:811-25
5. Sheen AJ et al. 2003. Br. J. Cancer. 88(7):1119-27
6. Francis RJ et al. 2002. Br. J. Cancer. 87(6): 600-607
7. Cooke SP et al. 2002. Bioconjug. Chem. 13(1):7-15
8. Chowdhury S et al. 2004. Mol. Ther. 9(1):85-92
9. Huhalov A et al. British Association of Cancer Research 2004 Annual Meeting
10. Begent RH et al. 1996. Nat. Med. 2(9):979-84
11. Verhaar MJ et al. 1996. J. Nuclear Med. 37:868-872

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