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.<ref>,

 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, 
 1984,
 Vol. 160(Issue: 6),
 pp. 1686–1701,
 DOI: 10.1084/jem.160.6.1686,
 PMID: 6239899,
 PMC: 2187539,</ref><ref>, 
 Preparation and performance of bispecific F(ab' gamma)2 antibody containing thioether-linked Fab' gamma fragments, 
 Journal of Immunology, 
 1987,
 Vol. 139(Issue: 7),
 pp. 2367–2375,
 
 PMID: 2958547,</ref> 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.<ref name="Borchmann">, 
 Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma, 
 Blood, 
 2002,
 Vol. 100(Issue: 9),
 pp. 3101–3107,
 DOI: 10.1182/blood-2001-12-0295,
 PMID: 12384405,</ref>

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,<ref name="Borchmann" /><ref>,

 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, 
 1998,
 Vol. 77(Issue: 2),
 pp. 251–256,
 DOI: <251::AID-IJC14>3.0.CO;2-E 10.1002/(SICI)1097-0215(19980717)77:2<251::AID-IJC14>3.0.CO;2-E,</ref> but the concept was dropped because of high production costs.<ref>

Entwicklung und Charakterisierung bispezifischer Antikörper-Derivate zur Immuntherapie CD19-positiver Leukämien und Lymphome(link). {{{website}}}. Friedrich-Alexander-Universität.

Erlangen-Nürnberg.

</ref>

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

References

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