Chemically linked Fab

File:Chemically linked Fab'.svgs 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.{{Cite journal

| doi = 10.1084/jem.160.6.1686

| last1 = Karpovsky | first1 = B.

| last2 = Titus | first2 = J. A.

| last3 = Stephany | first3 = D. A.

| last4 = Segal | first4 = D. M.

| title = Production of target-specific effector cells using hetero-cross-linked aggregates containing anti-target cell and anti-Fc gamma receptor antibodies

| journal = The Journal of Experimental Medicine

| volume = 160

| issue = 6

| pages = 1686–1701

| year = 1984

| pmid = 6239899

| pmc = 2187539

}}{{Cite journal

| pmid = 2958547

| year = 1987

| last1 = Glennie | first1 = M. J.

| last2 = McBride | first2 = H. M.

| last3 = Worth | first3 = A. T.

| last4 = Stevenson | first4 = G. T.

| title = Preparation and performance of bispecific F(ab' gamma)2 antibody containing thioether-linked Fab' gamma fragments

| volume = 139

| issue = 7

| pages = 2367–2375

| journal = Journal of Immunology

| doi = 10.4049/jimmunol.139.7.2367

}} 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.{{Cite journal

| doi = 10.1182/blood-2001-12-0295

| title = Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma

| year = 2002 | first11 = A.

| last1 = Borchmann

| last11 = Engert | first1 = P.

| journal = Blood

| volume = 100 | first10 = V.

| pages = 3101–3107

| last2 = Schnell | first2 = R.

| last3 = Fuss | first3 = I.

| last4 = Manzke

| last10 = Diehl | first4 = O.

| last5 = Davis | first5 = T.

| last6 = Lewis | first6 = L. D.

| last7 = Behnke | first7 = D.

| last8 = Wickenhauser | first8 = C.

| last9 = Schiller | first9 = P.

| pmid = 12384405

| issue = 9

| doi-access = free

}}

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,{{Cite journal

| doi = 10.1002/(SICI)1097-0215(19980717)77:2<251::AID-IJC14>3.0.CO;2-E

| title = 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

| year = 1998

| last1 = Link | first1 = B. K.

| last2 = Kostelny | first2 = S. A.

| last3 = Cole | first3 = M. S.

| last4 = Fusselman | first4 = W. P.

| last5 = Tso | first5 = J. Y.

| last6 = Weiner | first6 = G. J.

| journal = International Journal of Cancer

| volume = 77

| issue = 2

| pages = 251–256

| pmid = 9650561

| doi-access = free

}} but the concept was dropped because of high production costs.{{cite thesis|first1=C|last1=Kellner|url=http://www.opus.ub.uni-erlangen.de/opus/volltexte/2009/1235/|title=Entwicklung und Charakterisierung bispezifischer Antikörper-Derivate zur Immuntherapie CD19-positiver Leukämien und Lymphome|trans-title=Development and characterisation of bispecific antibody derivatives for the immunotherapy of CD19-positive leukaemia and lymphoma|language=German, English|publisher=Friedrich-Alexander-Universität|location=Erlangen-Nürnberg|year=2008}}

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