Naturally occurring antibodies devoid of light chains

Hamers-Casterman, C; Atarhouch, Touriya; Muyldermans, Serge; Robinson, Gordon W.; Hamers, casterman C; Eb, Songa; Bendahman, Najib; Hamers, R.

doi:10.1038/363446a0

Cited by 2,671 publications

(1,919 citation statements)

References 20 publications

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“…In this context, the heavychain camelid antibody fragments appear to be of particular interest. Camelids (camels, dromedaries and llamas) generate functional antibodies consisting only of two heavy chains; the latter also differ from the corresponding regions of conventional antibodies in that they lack the CH1 domain [110]. Since they are devoid of the light chains of conventional antibodies, the antigen binding site of these "heavychain" antibodies is limited to a single-domain, referred to as the V H H domain.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin

Dobson

2004

Biochimie

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The deposition of proteins in the form of amyloid fibrils is the characteristic feature of more than 20 medical conditions affecting the central nervous system or a variety of peripheral tissues. These disorders, which include Alzheimer's disease, the prion diseases and type II diabetes, are of enormous importance in the context of present-day human health and welfare. Extensive research is therefore being carried out to define the molecular details of the mechanism of the pathological conversion of amyloidogenic proteins from their soluble forms into fibrillar structures. This review focuses on recent studies that demonstrate the power of using antibodies or antibody fragments to probe the process of fibril formation, and discusses the emerging potential of these species as diagnostic and therapeutic agents.

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Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin

Dobson

2004

Biochimie

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“…The concept of autonomous, antigen binding-competent sdAbs was first described by Ward et al . in 1989, 2 and several years later, naturally-occurring antibodies lacking light chains were discovered in dromedary camels 3 and nurse sharks. 4 The ~12–15 kDa variable domains of these antibodies (V H Hs and V NAR s, respectively; Figure 1) can be produced recombinantly and can recognize antigen in the absence of the remainder of the antibody heavy chain.…”

Section: Introductionmentioning

confidence: 99%

Antigen recognition by single-domain antibodies: structural latitudes and constraints

Henry

MacKenzie

2018

mAbs

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Single-domain antibodies (sdAbs), the autonomous variable domains of heavy chain-only antibodies produced naturally by camelid ungulates and cartilaginous fishes, have evolved to bind antigen using only three complementarity-determining region (CDR) loops rather than the six present in conventional VH:VL antibodies. It has been suggested, based on limited evidence, that sdAbs may adopt paratope structures that predispose them to preferential recognition of recessed protein epitopes, but poor or non-recognition of protuberant epitopes and small molecules. Here, we comprehensively surveyed the evidence in support of this hypothesis. We found some support for a global structural difference in the paratope shapes of sdAbs compared with those of conventional antibodies: sdAb paratopes have smaller molecular surface areas and diameters, more commonly have non-canonical CDR1 and CDR2 structures, and have elongated CDR3 length distributions, but have similar amino acid compositions and are no more extended (interatomic distance measured from CDR base to tip) than conventional antibody paratopes. Comparison of X-ray crystal structures of sdAbs and conventional antibodies in complex with cognate antigens showed that sdAbs and conventional antibodies bury similar solvent-exposed surface areas on proteins and form similar types of non-covalent interactions, although these are more concentrated in the compact sdAb paratope. Thus, sdAbs likely have privileged access to distinct antigenic regions on proteins, but only owing to their small molecular size and not to general differences in molecular recognition mechanism. The evidence surrounding the purported inability of sdAbs to bind small molecules was less clear. The available data provide a structural framework for understanding the evolutionary emergence and function of autonomous heavy chain-only antibodies.

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“…The aim of our study is to use single-domain antibody fragments (VHHs) for such immunotherapy (Harmsen et al 2005). VHHs are derived from camelid heavy chain antibodies and are naturally devoid of light chains (Hamers-Casterman et al 1993). They have a high physicochemical stability (Van der Linden et al 1999) and are well expressed in microorganisms .…”

Section: Introductionmentioning

confidence: 99%

Selection and optimization of proteolytically stable llama single-domain antibody fragments for oral immunotherapy

Harmsen

Solt

Bemmel³

et al. 2006

Appl Microbiol Biotechnol

107

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We previously demonstrated that oral application of the recombinant single-domain antibody fragment (VHH) clone K609, directed against Escherichia coli F4 fimbriae, reduced E. coli-induced diarrhoea in piglets, but only at high VHH doses. We have now shown that a large portion of the orally applied K609 VHH is proteolytically degraded in the stomach. Stringent selection for proteolytic stability identified seven VHHs with 7-to 138-fold increased stability after in vitro incubation in gastric fluid. By DNA shuffling we obtained four clones with a further 1.5-to 3-fold increased in vitro stability. These VHHs differed by at most ten amino acid residues from each other and K609 that were scattered over the VHH sequence and did not overlap with predicted protease cleavage sites. The most stable clone, K922, retained 41% activity after incubation in gastric fluid and 90% in jejunal fluid. Oral application of K922 to piglets confirmed its improved proteolytic stability. In addition, K922 bound to F4 fimbriae with higher affinity and inhibited fimbrial adhesion at lower VHH concentrations. K922 is thus a promising candidate for prevention of piglet diarrhoea. Furthermore, our findings could guide selection and improvement by genetic engineering of other recombinant antibody fragments for oral use.

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Naturally occurring antibodies devoid of light chains

Cited by 2,671 publications

References 20 publications

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Antigen recognition by single-domain antibodies: structural latitudes and constraints

Selection and optimization of proteolytically stable llama single-domain antibody fragments for oral immunotherapy

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