Generation of high-affinity human antibodies by combining donor-derived and synthetic complementarity-determining-region diversity
| Autor: | Hennie R. Hoogenboom, Edward H. Cohen, Shannon Hogan, Isaac J. Rondon, Malini Viswanathan, Jennifer A. Leeds, Robert Charles Ladner, Andrew E. Nixon, Marc Daukandt, Rachel Baribault Kent, Sonia Schoonbroodt, Nicole Coolen-van Neer, Nastri Horacio G, Guannan Kuang, Daniel J. Sexton, Lili Huang, Kristin L. Rookey, Louise Rem, Irina Kashin, Rob van Hegelsom, Mieke Steukers, Simon E. Hufton, Mary Devlin, Henk Pieters, Nicolas Frans, Rene Hoet |
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| Rok vydání: | 2005 |
| Předmět: |
Phage display
Antibody Affinity Biomedical Engineering Somatic hypermutation Bioengineering Complementarity determining region Computational biology Plasma protein binding Protein Engineering Applied Microbiology and Biotechnology Affinity maturation Immunoglobulin Fab Fragments Antigen Peptide Library Humans Peptide library Recombination Genetic biology Genetic Variation Complementarity Determining Regions Virology Tissue Donors Antibody Formation biology.protein Molecular Medicine Antibody Protein Binding Biotechnology |
| Zdroj: | Nature Biotechnology. 23:344-348 |
| ISSN: | 1546-1696 1087-0156 |
| Popis: | Combinatorial libraries of rearranged hypervariable V(H) and V(L) sequences from nonimmunized human donors contain antigen specificities, including anti-self reactivities, created by random pairing of V(H)s and V(L)s. Somatic hypermutation of immunoglobulin genes, however, is critical in the generation of high-affinity antibodies in vivo and occurs only after immunization. Thus, in combinatorial phage display libraries from nonimmunized donors, high-affinity antibodies are rarely found. Lengthy in vitro affinity maturation is often needed to improve antibodies from such libraries. We report the construction of human Fab libraries having a unique combination of immunoglobulin sequences captured from human donors and synthetic diversity in key antigen contact sites in heavy-chain complementarity-determining regions 1 and 2. The success of this strategy is demonstrated by identifying many monovalent Fabs against multiple therapeutic targets that show higher affinities than approved therapeutic antibodies. This very often circumvents the need for affinity maturation, accelerating discovery of antibody drug candidates. |
| Databáze: | OpenAIRE |
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