2021, Volume 7, Issue 11
Engineering >> 2021, Volume 7, Issue 11 doi: 10.1016/j.eng.2020.10.024
A Novel Human Antibody, HF, against HER2/erb-B2 Obtained by a Computer-Aided Antibody Design Method
a State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing 100850, China
b Beijing Key Laboratory of Therapeutic Gene Engineering Antibody, Beijing 100850, China
c Institute of Military Cognitive and Brain Sciences, Beijing 100850, China
d Beijing Mabworks Biotech Co. Ltd., Beijing 100176, China
e Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China
Next Previous
Abstract
Fully human antibodies have minimal immunogenicity and safety profiles. At present, most potential antibody drugs in clinical trials are humanized or fully human. Human antibodies are mostly generated using the phage display method (in vitro) or by transgenic mice (in vivo); other methods include B lymphocyte immortalization, human–human hybridoma, and single-cell polymerase chain reaction. Here, we describe a structure-based computer-aided de novo design technology for human antibody generation. Based on the complex structure of human epidermal growth factor receptor 2 (HER2)/Herceptin, we first designed six short peptides targeting the potential epitope of HER2 recognized by Herceptin. Next, these peptides were set as complementarity determining regions in a suitable immunoglobulin frame, giving birth to a novel anti-HER2 antibody named “HF,” which possessed higher affinity and more effective anti-tumor activity than Herceptin. Our work offers a useful tool for the quick design and selection of novel human antibodies for basic mechanical research as well as for imaging and clinical applications in immune-related diseases, such as cancer and infectious diseases.
Keywords
SupplementaryMaterials
Figures
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
References
[ 1 ] Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004;3(5):391–400. link1
[ 2 ] Reichert JM, Valge-Archer VE. Development trends for monoclonal antibody cancer therapeutics. Nat Rev Drug Discov 2007;6(5):349–56. link1
[ 3 ] Lippow SM, Wittrup KD, Tidor B. Computational design of antibody-affinity improvement beyond in vivo maturation. Nat Biotechnol 2007;25(10):1171–6. link1
[ 4 ] Clark LA, Boriack-Sjodin PA, Eldredge J, Fitch C, Friedman B, Hanf KJM, et al. Affinity enhancement of an in vivo matured therapeutic antibody using structure-based computational design. Protein Sci 2006;15(5):949–60. link1
[ 5 ] Lazar GA, Dang W, Karki S, Vafa O, Peng JS, Hyun L, et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA 2006;103 (11):4005–10. link1
[ 6 ] Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol 2006;6 (5):343–57. link1
[ 7 ] Caravella JA, Wang D, Glaser SM, Lugovskoy A. Structure-guided design of antibodies. Curr Comput Aided Drug Des 2010;6(2):128–38. link1
[ 8 ] Chang H, Qin W, Li Y, Zhang J, Lin Z, Lv M, et al. A novel human scFv fragment against TNF-a from de novo design method. Mol Immunol 2007;44 (15):3789–96. link1
[ 9 ] Geng S, Chang H, Qin W, Lv M, Li Y, Feng J, et al. A novel anti-TNF scFv constructed with human antibody frameworks and antagonistic peptides. Immunol Res 2015;62(3):377–85. link1
[10] Qin W, Feng J, Li Y, Lin Z, Shen B. De novo design TNF-a antagonistic peptide based on the complex structure of TNF-a with its neutralizing monoclonal antibody Z12. J Biotechnol 2006;125(1):57–63. link1
[11] Qin W, Feng J, Li Y, Lin Z, Shen B. A novel domain antibody rationally designed against TNF-a using variable region of human heavy chain antibody as scaffolds to display antagonistic peptides. Mol Immunol 2007;44(9):2355–61. link1
[12] Tagliabue E, Balsari A, Campiglio M, Pupa SM. HER2 as a target for breast cancer therapy. Expert Opin Biol Ther 2010;10(5):711–24. link1
[13] Garnock-Jones KP, Keating GM, Scott LJ. Trastuzumab: a review of its use as adjuvant treatment in human epidermal growth factor receptor 2 (HER2) positive early breast cancer. Drugs 2010;70(2):215–39. link1
[14] Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 2009;14(4):320–68. link1
[15] Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003;421(6924):756–60.
[16] Tomasevic N, Luehrsen K, Baer M, Palath V, Martinez D, Williams J, et al. A high affinity recombinant antibody to the human EphA3 receptor with enhanced ADCC activity. Growth Factors 2014;32(6):223–35.
[17] Gu X, Jia X, Feng J, Shen B, Huang Y, Geng S, et al. Molecular modeling and affinity determination of scFv antibody: proper linker peptide enhances its activity. Ann Biomed Eng 2010;38(2):537–49. link1
[18] Jorgensen WL. The many roles of computation in drug discovery. Science 2004;303(5665):1813–8. link1
[19] Crameri A, Cwirla S, Stemmer WPC. Construction and evolution of antibodyphage libraries by DMA shuffling. Nat Med 1996;2(1):100–2. link1
[20] Hanes J, Jermutus L, Weber-Bornhauser S, Bosshard HR, Pluckthun A. Ribosome display efficiently selects and evolves high-affinity antibodies in vitro from immune libraries. Proc Natl Acad Sci USA 1998;95(24):14130–5. link1
[21] Chevalier BS, Kortemme T, Chadsey MS, Baker D, Monnat RJ, Stoddard BL. Design, activity, and structure of a highly specific artificial endonuclease. Mol Cell 2002;10(4):895–905. link1
[22] Kuhlman B, Dantas G, Ireton GC, Varani G, Stoddard BL, Baker D. Design of a novel globular protein fold with atomic-level accuracy. Science 2003;302 (5649):1364–8. link1
[23] Dwyer MA, Looger LL, Hellinga HW. Computational design of a biologically active enzyme. Science 2004;304(5679):1967–71. link1
[24] Kortemme T, Joachimiak LA, Bullock AN, Schuler AD, Stoddard BL, Baker D. Computational redesign of protein–protein interaction specificity. Nat Struct Mol Biol 2004;11(4):371–9. link1
[25] He W, Qiang M, Ma W, Valente AJ, Quinones MP, Wang W, et al. Development of a synthetic promoter for macrophage gene therapy. Hum Gene Ther 2006;17(9):949–59. link1
[26] Pantazes RJ, Grisewood MJ, Maranas CD. Recent advances in computational protein design. Curr Opin Struct Biol 2011;21(4):467–72. link1
京公网安备 11010502051620号
