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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2016.3
- 수록면
- 217 - 228 (12page)
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To generate a biobetter that has improved therapeutic activity, we constructed scFv libraries via random mu-tagenesis of several residues of CDR-H3 and -L3 of hu4D5. The scFv clones were isolated from the phage display libraries by stringent panning, and their anti-proliferative activity against HER2-positive cancer cells was evaluated as a primary selection criterion. Conse-quently, we selected AH06 as a biobetter antibody that had a 7.2-fold increase in anti-proliferative activity (IC50: 0.81 nM) against the gastric cancer cell line NCI-N87 and a 7.4-fold increase in binding affinity (KD: 60 pM) to HER2 compared to hu4D5. The binding energy calculation and molecular modeling suggest that the substitution of residues of CDR-H3 to W98, F100c, A101 and L102 could stabilize binding of the antibody to HER2 and there could be direct hydrophobic interactions between the aromatic ring of W98 and the aliphatic group of I613 within HER2 domain IV as well as the heavy and light chain hydrophobic interactions by residues F100c, A101 and L102 of CDR-H3. Therefore, we speculate that two such interactions were exerted by the residues W98 and F100c. A101 and L102 may have a synergistic effect on the increase in the binding affinity to HER2. AH06 specifically binds to domain IV of HER2, and it decreased the phosphorylation level of HER2 and AKT. Above all, it highly increased the overall level of p27 compared to hu4D5 in the gastric cancer cell line NCI-N82, suggesting that AH06 could potentially be a more efficient therapeutic agent than hu4D5.
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참고문헌 (31)
참고문헌 신청
Back, H. / 2002 / An improved helper phage system for efficient isolation of specific antibody molecules in phage display / Nucleic Acids Res 30:18~26
Carter, P. / 1992 / Humanization of an anti-p185 HER2 antibody for human cancer therapy / Proc. Natl. Acad. Sci. USA 89:4285~4289
Chatellier, J. / 1996 / Functional mapping of conserved residues located at the VL and VH domain interface of a Fab / J. Mol. Biol 264:1~6
Chen, Y. / 1999 / Selection and analysis of an optimized anti-VEGF antibody crystal structure of an affinity-matured Fab in complex with antigen / J. Mol. Biol 293:865~881
Genentech, Inc. / 2005 / Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies / US6949245 (US Patent)
Carter, P. / 1992 / Humanization of an anti-p185 HER2 antibody for human cancer therapy / Proc. Natl. Acad. Sci. USA 89:4285~4289
Chatellier, J. / 1996 / Functional mapping of conserved residues located at the VL and VH domain interface of a Fab / J. Mol. Biol 264:1~6
Chen, Y. / 1999 / Selection and analysis of an optimized anti-VEGF antibody crystal structure of an affinity-matured Fab in complex with antigen / J. Mol. Biol 293:865~881
Genentech, Inc. / 2005 / Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies / US6949245 (US Patent)
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