期刊
NATURE BIOTECHNOLOGY
卷 23, 期 3, 页码 344-348出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt1067
关键词
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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(1,2). 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(3-6). This very often circumvents the need for affinity maturation, accelerating discovery of antibody drug candidates.
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