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Invited Mini Review : Synthetic approach to the generation of antibody diversity
( Hyunbo Shim ) 생화학분자생물학회 2015 BMB Reports Vol.48 No.9
The in vitro antibody discovery technologies revolutionized the generation of target-specific antibodies that traditionally relied on the humoral response of immunized animals. An antibody library, a large collection of diverse, pre-constructed antibodies, can be rapidly screened using in vitro display technologies such as phage display. One of the keys to successful in vitro antibody discovery is the quality of the library diversity. Antibody diversity can be obtained either from natural B-cell sources or by the synthetic methods that combinatorially generate random nucleotide sequences. While the functionality of a natural antibody library depends largely upon the library size, various other factors can affect the quality of a synthetic antibody library, making the design and construction of synthetic antibody libraries complicated and challenging. In this review, we present various library designs and diversification methods for synthetic antibody library. From simple degenerate oligonucleotide synthesis to trinucleotide synthesis to physicochemically optimized library design, the synthetic approach is evolving beyond the simple emulation of natural antibodies, into a highly sophisticated method that is capable of producing high quality antibodies suitable for therapeutic, diagnostic, and other demanding applications. [BMB Reports 2015; 48(9): 489-494]
Next generation antibody therapeutics:
Thi Thu Ha Nguyen,Xuelian Bai,Hyunbo Shim 한국구조생물학회 2015 Biodesign Vol.3 No.4
A new generation of therapeutic antibody technologies has emerged last decade, most notable among which are bispecific antibodies and antibody-drug conjugates. Traditional monoclonal antibodies recognize a single target molecule and exert their therapeutic activity by neutralizing the target and/or through the effector functions. On the other hand, bispecific antibodies of various formats are able to bind two different targets simultaneously. Two major approaches to harness their bispecific binding activity for therapeutic application are being pursued: recruitment of immune effector cells to the diseased cells, and simultaneous/synergistic neutralization of two disease-causing molecules. Antibody-drug conjugates are disease-targeting monoclonal antibodies chemically conjugated to a highly cytotoxic compound. The internalization of the conjugate by endocytosis and subsequent release of the cytotoxin result in a potent and selective cytotoxic activity against cancerous target cells. Optimization of the drug, linker, and conjugation chemistry is a major technological challenge in developing antibody-drug conjugates. Despite their relatively recent emergence and technological difficulties, a few examples of these novel therapeutic modalities have been successfully developed and commercialized, and many others are in the late stages of clinical development. In this review, the background and the current status of technological development in this field is discussed, with emphasis on the detailed molecular design of these molecules.
Na, Jung-Hyun,Joo, Man-Seok,Lee, Won-Kyu,Shim, Hyunbo,Lim, Si-Hyung,Jung, Sang Taek,Yu, Yeon Gyu Korean Chemical Society 2013 Bulletin of the Korean Chemical Society Vol.34 No.2
Single-chain variable fragments of antibodies (scFv) specific to 2,4-dinitrotoluene (DNT) were isolated from a phage library displaying synthetic human scFv fragments with 6 diversified complementary determining regions (CDRs). A DNT derivative that contained an extended amine group was synthesized and conjugated to the NHS-group that was linked to magnetic beads. Phages specific to the immobilized DNT derivatives were isolated from the library after 4 rounds of sequential binding and elution processes. The displayed scFv fragments from the isolated phages showed consensus CDR sequences. One DNT-specific scFv was expressed in E. coli and purified using Ni-affinity chromatography. The purified DNT-specific scFv binds specifically to the immobilized DNT-derivative with $K_D$ value of $6.0{\times}10^{-7}$ M. The scFv and DNT interaction was not disrupted by the addition of 4-nitrotoluene or benzoic acid. These data demonstrate that the screened scFv from the phage displayed library could be used for selective and sensitive detection of explosives such as TNT.
Kim, Mi Ra,Jang, Ji Hye,Park, Chang Sik,Kim, Taek-Keun,Kim, Youn-Jae,Chung, Junho,Shim, Hyunbo,Nam, In Hyun,Han, Jung Min,Lee, Sukmook MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.3
<P>Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung tissue, and high VCAM-1 expression correlated with poor survival in lung cancer patients. VCAM-1 knockdown reduced migration of A549 human lung cancer cells into Matrigel, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1 mediated A549 cell migration into Matrigel. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed the migration of A549 and NCI-H1299 lung cancer cell lines into Matrigel. Taken together, these results suggest that VCAM-1-D6 is a key domain for regulating VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion.</P>