Human monoclonal antibodies are important for the development of inhibitors, vaccines, diagnostic and research tools. Previously a large non-immune human antibody library (15 billion (15 x 10⁹) clones) was constructed from the lymph nodes, spleen and peripheral blood lymphocytes of 50 donors. One antibody, isolated from this library, includes a stop codon in the light chain but was still expressed and included a functional heavy chain. The VH domain exhibits high levels of expression and high solubility even in the absence of a light chain variable domain. This VH domain was used as a framework to construct a large human VH domain library (25 billion clones) by grafting naturally occurring complementarity determining regions (CDRs) from other human antibody libraries and randomly mutating one of the CDRs. This library has been used internally for selecting anti-HIV antibodies, viruses of biodefense interest and cancer-related antigens and is available for licensing as a biological material. Several high-affinity binders have already been identified.

The antibodies generated from this library are small (e.g., about more than 14 kDa), highly stable and can be expressed at high levels as monomers. The library permits the isolation of antibodies with favorable properties: affinity, stability, solubility, high levels of expression (at low cost), low rejection rates and low toxicity.

Applications:

• Antibody discovery
• Therapeutics
• Diagnostics
• Research Materials

Relevant Publications:

1. W Chen et al. Construction of a large phage-displayed human antibody domain library with a scaffold based on a newly identified highly soluble, stable heavy chain variable domain. J Mol Biol. 2008 Jul 06; Epub ahead of print, doi:10.1016/j.jmb.2008.07.054.  [PubMed abs]
2. P Jirholt et al. Exploiting sequence space: shuffling in vivo formed complementarity determining regions into a master framework. Gene. 1998 Jul 30;215(2):471-476.  [PubMed abs]
3. Y Reiter et al. An antibody single-domain phage display library of a native heavy chain variable region: isolation of functional single-domain VH molecules with a unique interface. J Mol Biol. 1999 Jul 16;290(3):685-698.  [PubMed abs]
4. E Söderlind et al. Recombining germline-derived CDR sequences for creating diverse single framework antibody libraries. Nat Biotechnol. 2000 Aug 18;18(8):852-856.  [PubMed abs]
5. LJ Holt et al. Domain antibodies: proteins for therapy. Trends Biotechnol. 2003 Nov;21(11):484-490.  [PubMed abs]
6. L Riechmann and S Muyldermans. Single domain antibodies: comparison of camel VH and camelised human VH domains. J Immunol Methods. 1999 Dec 10;231(1-2)25-38.  [PubMed abs]

HHS Reference No. E-037-2008/0 - Research Tool. Patent protection is not being pursued for this technology.

Inventors:

Dimiter S. Dimitrov and Weizao Chen (NCI)

Licensing Status:

Available for licensing.

Collaborative Research Opportunity:

The National Cancer Institute’s Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Large Semi-Synthetic Human Antibody Domain Library. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.