Chemically linked Fab

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]

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.

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 similar 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.
  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. 139 (7): 2367–2375. PMID 2958547.
  3. Borchmann, P.; Schnell, R.; Fuss, I.; Manzke, O.; Davis, T.; Lewis, L. D.; Behnke, D.; Wickenhauser, C.; Schiller, P.; Diehl, V.; Engert, A. (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.
  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): 251–256. doi:10.1002/(SICI)1097-0215(19980717)77:2<251::AID-IJC14>3.0.CO;2-E. PMID 9650561.
  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] (Thesis) (in German and English). Erlangen-Nürnberg: Friedrich-Alexander-Universität.


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