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Creative Biolabs is a well-recognized leader in single domain antibody (sdAb) library construction and screening services. Our unique services including:
Why single domain antibodies are preferred?
Single domain antibodies represent the smallest antibody that was proven of diagnostic and therapeutic usefulness. They are antibody fragments that engineered from single monomeric variable domains of either camelids’ heavy-chain antibody (VHH) or cartilaginous fishes’ IgNAR (VNAR). On the other hand, it is also possible to develop single domain antibodies from camelized human antibodies.
In particular, single domain antibodies combine the benefits of conventional antibodies with important features of small molecule drugs. They are able to bind to hidden epitopes that are not accessible to whole antibodies. In addition, in comparison with small molecule drugs that target enzyme active sites and receptor clefts, single domain antibodies have the potential of greater affinity and selectivity, thus promising lower side effect and better efficacy. Furthermore, because of their small size (they are only 1/10 the size of a whole antibody), single domain antibodies can penetrate tissues faster than other antibodies and even break through the blood-brain barrier (BBB), which turns them into excellent candidates for central nervous system disease therapies. Single domain antibodies have higher stability during the changes of temperature and chemical environments and great potential for gastrointestinal stability and oral availability. Also, thanks to its simple nature of a single-chain peptide, single domain antibodies have exceptional drug format flexibility and allow efficient drug discovery and development.
Fig.1 The comparison among single domain antibody and other types of antibody.
In terms of the advanced phage display technology, Creative Biolabs has unparalleled capabilities for the construction of VHH or VNAR based single domain antibody libraries through immunized camel, llama, alpaca or shark. In comparison with naïve libraries, immune libraries usually produce antibodies of greater affinity, thus avoiding time-consuming in vitro antibody affinity maturation effort. Antibodies from naïve libraries frequently require affinity maturation before they are useful due to affinity issues. Furthermore, in comparison with naïve libraries, which usually require a size of 1-10 billion independent clones to be useful, an immune library can be much smaller. Our experience showed that immune libraries with a size of 1-10 million variants could be sufficient to produce excellent antibodies.
Our scientists have extensive experience in cloning the single domain antibody repertoire from immunized plasma cells into our phage display vectors. By reverse transcription and polymerase chain reaction, a library of single domain antibodies containing 10-100 million clones is regularly produced.
Fig.2 The structure of IgNAR and VNAR. (Nuttall 2012)
Creative Biolabs also has sufficient expertise in constructing synthetic naïve single domain antibody libraries. By nature, single domain antibodies developed from either VHH or VNAR are more stable and soluble, although their immunogenicity can be higher than single domain antibodies engineered from human antibodies. If the immunogenicity of the single domain antibodies is not a concern, a synthetic VHH or VNAR single domain antibody library can be made by randomizing the CDR1 and CDR3 using trimer codon technology.
In case the immunogenicity of single domain antibodies is a concern, our services allow the construction of camelized human single domain antibody libraries which are based on the monomerization of human antibody heavy chain framework. The binding region of normal human IgG consists of two domains (VH and VL) which tend to dimerize or aggregate because of their lipophilicity; the monomerization will be accomplished by replacing lipophilic with hydrophilic amino acids at a few proprietary positions. Such synthetic libraries represent a good source of single domain antibodies against self, non-immunogenic, and toxic antigens since the libraries are usually sufficiently vast and diverse.
To select interested single domain antibodies with high affinity and specificity, scientists from Creative Biolabs can offer high-quality screening service for phage-displayed sdAb libraries. In particular, we are specialized in isolating single domain antibody inhibitors that can access cavities within molecular targets such as enzyme active sites and receptor clefts. Meanwhile, a method based on heat denaturation of single domain antibodies on the surface of phage has also been developed to select non-aggregating single domain antibodies.
Creative Biolabs has established the novel sdAb production platforms that enable the generation of target-specific single domain antibodies within 8 weeks. We have produced a large number of single domain antibodies with high affinity and specificity against a large number of distinct targets, including cytokines, cell surface receptors, tumor cell markers, viral antigens, and enzymes. Of note, single domain antibodies are perfectly stable polypeptides harboring the full antigen-binding capacity of conventional antibodies. This unique structural and functional property render these molecules ideal candidates for new generation of antibody therapeutics.
To meet the special needs of our clients on single domain antibody, Creative Biolabs has combined our cutting-edge techniques with advanced phage display technology to offer a series of services including sdAb library construction, screening, and sdAb production. Our scientists are confident in tailoring the most appropriate protocol to develop high-quality single domain antibodies for our clients’ research purpose.
Nuttall, S. D. (2012) 'Overview and discovery of IgNARs and generation of VNARs', Single Domain Antibodies: Methods and Protocols, 27-36.
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