Chemically linked Fab

Example of chemically linked Fabs: two Fab' fragments linked with a thioether, resulting in a F(ab')₂. The molecule is bound to a tumour cell via the tumour antigen CD30 and to a macrophage via an Fc receptor.

Two chemically linked fragments antigen-binding form an artificial antibody that binds to two different antigens, making it a type of bispecific antibody. They are fragments antigen-binding (Fab or Fab') of two different monoclonal antibodies and are linked by chemical means like a thioether.^[1][2] Typically, one of the Fabs binds to a tumour antigen (such as CD30) and the other to a protein on the surface of an immune cell, for example an Fc receptor on a macrophage. In this way, tumour cells are attached to immune cells, which destroy them.^[3]

In the late 1990s and early 2000s, clinical trials with chemically linked Fabs were conducted for the treatment of various types of cancer. Early results were promising,^[3][4] but the concept was dropped because of high production costs.^[5]

Bi-specific T-cell engagers employ a smilar mechanism of action while being cheaper.

References

1. ^ Karpovsky, B.; Titus, J. A.; Stephany, D. A.; Segal, D. M. (1984). "Production of target-specific effector cells using hetero-cross-linked aggregates containing anti-target cell and anti-Fc gamma receptor antibodies". The Journal of experimental medicine 160 (6): 1686–1701. doi:10.1084/jem.160.6.1686. PMC 2187539. PMID 6239899. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2187539.  edit
2. ^ Glennie, M. J.; McBride, H. M.; Worth, A. T.; Stevenson, G. T. (1987). "Preparation and performance of bispecific F(ab' gamma)2 antibody containing thioether-linked Fab' gamma fragments". Journal of immunology (Baltimore, Md. : 1950) 139 (7): 2367–2375. PMID 2958547.  edit
3. ^ ^{a b} Borchmann, P.; Schnell, R.; Fuss, I.; Manzke, O.; Davis, T.; Lewis, L. D.; Behnke, D.; Wickenhauser, C. et al. (2002). "Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma". Blood 100 (9): 3101–3107. doi:10.1182/blood-2001-12-0295. PMID 12384405.  edit
4. ^ Link, B. K.; Kostelny, S. A.; Cole, M. S.; Fusselman, W. P.; Tso, J. Y.; Weiner, G. J. (1998). "Anti-CD3-based bispecific antibody designed for therapy of human B-cell malignancy can induce T-cell activation by antigen-dependent and antigen-independent mechanisms". International Journal of Cancer 77 (2): 251. doi:10.1002/(SICI)1097-0215(19980717)77:2<251::AID-IJC14>3.0.CO;2-E.  edit
5. ^ Kellner, C (2008). "Entwicklung und Charakterisierung bispezifischer Antikörper-Derivate zur Immuntherapie CD19-positiver Leukämien und Lymphome [Development and characterisation of bispecific antibody derivatives for the immunotherapy of CD19-positive leukaemia and lymphoma]" (in German and English). Erlangen-Nürnberg: Friedrich-Alexander-Universität. http://www.opus.ub.uni-erlangen.de/opus/volltexte/2009/1235/. 

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