In the past 50 years, there has been a great progress made in understanding and deploying antibodies in biology, medicine, and therapy. In this study, a brief overview is presented on how the crystal structures of antibody fragments guided therapeutic strategies emanating from our laboratories along with some historical perspective.
Get full access to this article
View all access options for this article.
References
1.
KöhlerG, MilsteinC: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature, 1975; 256:495–497.
2.
HershgoldEJ, CordobaF, CharacheP, GitlinD: A crystalline fragment from human gamma-globulin. Nature, 1963; 199:284–285.
3.
Hughes-JonesNC: Nature of the reaction between antigen and antibody. Br Med Bullerin, 1963; 19:171–177.
4.
PorterRR: Chemical structure of gamma-globulin and antibodies. Br Med Bullerin, 1964; 19:197–201.
5.
EdelmanGM, PoulikMD: Studies on structural units of the gamma-globulins. J Exp Med, 1961; 113:861–884.
6.
PorterRR: The hydrolysis of rabbit y-globulin and antibodies with crystalline papain. Biochem J, 1959; 73:119–126.
7.
WuTT, KabatEA: Pillars article: An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J Exp Med, 1970; 132:211–250.
8.
ColmanPM, EppO, FehlhammerH, BodeW, SchifferM, LattmanEE, JonesTA: X-ray studies on antibody fragments. FEBS Lett, 1974; 44:194–199.
9.
DaviesDR, PadlanEA, SegalDM: Three-dimensional structure of immunoglobulins. Ann Rev Biochem, 1975; 44:639–667.
10.
ChenCL, HsuJC, LinCW, WangCH, TsaiMH, WuCY, WongCH, MaC: Crystal structure of a homogeneous IgG-Fc glycoform with the N-glycan designed to maximize the antibody dependent cellular cytotoxicity. ACS Chem Biol, 2017; 12:1335–1345.
11.
LiY, WangG, LiN, WangY, ZhuQ, ChuH, WuW, TanY, YuF, SuX-D, GaoN, XiaoJ: Structural insights into immunoglobulin M. Science, 2020; 367:1014.
12.
SharpTH, BoyleAL, DiebolderCA, KrosA, KosterAJ, GrosP: Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b. Proc Natl Acad Sci U S A, 2019; 116:11900.
13.
StrongRK, CampbellR, RoseDR, PetskoGA, SharonJ, MargoliesMN: Three-dimensional structure of murine anti-p-azophenylarsonate Fab 36–71. 1. X-ray crystallography, site-directed mutagenesis, and modeling of the complex with hapten. Biochemistry, 1991; 30:3739–3748.
14.
ParkkinenT, NevanenTK, KoivulaA, RouvinenJ: Crystal structures of an enantioselective fab-fragment in free and complex forms. J Mol Biol, 2006; 357:471–480.
15.
FiorentiniS, MatczakE, GalloRC, ReitzMS, KeydarI, WatkinsBA: Humanization of an antibody recognizing a breast cancer specific epitope by CDR-grafting. Immunotechnology, 1997; 3:45–59.
GriffinL, LawsonA: Antibody fragments as tools in crystallography. Clin Exp Immunol, 2011; 165:285–291.
19.
Cowan-JacobSW, MöbitzH, FabbroD: Structural biology contributions to tyrosine kinase drug discovery. Curr Opin Cell Biol, 2009; 21:280–287.
20.
SkwarczynskaM, OttmannC: Protein-protein interactions as drug targets. Future Med Chem, 2015; 7:2195–2219.
21.
WangJ, YazdaniS, HanA, SchapiraM: Structure-based view of the druggable genome. Drug Discov Today, 2020; 25:561–567.
22.
KoshlandDE, Jr: Conformational changes: How small is big enough?. Nat Med, 1998; 4:1112–1114.
23.
HubbardPA, MoodyCL, MuraliR: Allosteric modulation of Ras and the PI3K/AKT/mTOR pathway: Emerging therapeutic opportunities. Front Physiol, 2014; 5:478.
24.
NeroTL, ParkerMW, MortonCJ: Protein structure and computational drug discovery. Biochem Soc Trans, 2018; 46:1367–1379.
25.
WilliamsWV, GuyHR, RubinDH, RobeyF, MyersJN, Kieber-EmmonsT, WeinerDB, GreeneMI: Sequences of the cell-attachment sites of reovirus type 3 and its anti-idiotypic/antireceptor antibody: Modeling of their three-dimensional structures. Proc Natl Acad Sci U S A, 1988; 85:6488–6492.
26.
MuraliR, GreeneMI: Structure-based design of immunologically active therapeutic peptides. Immunol Res, 1998; 17:163–169.
27.
ParkBW, ZhangHT, WuC, BerezovA, ZhangX, DuaR, WangQ, KaoG, O'RourkeDM, GreeneMI, MuraliR: Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine kinases in vitro and in vivo. Nat Biotechnol, 2000; 18:194–198.
28.
MuraliR, GreeneMI: Structure based antibody-like peptidomimetics. Pharmaceuticals (Basel), 2012; 5:209–235.
29.
MuraliR, ChengX, BerezovA, DuX, SchönA, FreireE, XuX, ChenYH, GreeneMI: Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107. Proc Natl Acad Sci U S A, 2005; 102:10970–10975.
30.
BerezovA, CaiZ, FreudenbergJA, ZhangH, ChengX, ThompsonT, MuraliR, GreeneMI, WangQ: Disabling the mitotic spindle and tumor growth by targeting a cavity-induced allosteric site of survivin. Oncogene, 2012; 31:1938–1948.
31.
RotinenM, YouS, YangJ, CoetzeeSG, Reis-SobreiroM, HuangWC, HuangF, PanX, YáñezA, HazelettDJ, ChuCY, SteadmanK, MorrisseyCM, NelsonPS, CoreyE, ChungLWK, FreedlandSJ, Di VizioD, GarrawayIP, MuraliR, KnudsenBS, FreemanMR: ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med, 2018; 24:1887–1898.
32.
LevineDH, GhoroghchianPP, FreudenbergJ, ZhangG, TherienMJ, GreeneMI, HammerDA, MuraliR: Polymersomes: A new multi-functional tool for cancer diagnosis and therapy. Methods, 2008; 46:25–32.
33.
DingH, GangalumPR, GalstyanA, FoxI, PatilR, HubbardP, MuraliR, LjubimovaJY, HollerE: HER2-positive breast cancer targeting and treatment by a peptide-conjugated mini nanodrug. Nanomedicine, 2017; 13:631–639.
34.
KozborD: Cancer vaccine with mimotopes of tumor-associated carbohydrate antigens. Immunol Res, 2010; 46:23–31.
35.
Monzavi-KarbassiB, ShamlooS, Kieber-EmmonsM, JousheghanyF, LuoP, LinKY, Cunto-AmestyG, WeinerDB, Kieber-EmmonsT: Priming characteristics of peptide mimotopes of carbohydrate antigens. Vaccine, 2003; 21:753–760.
36.
Kieber-EmmonsT, SahaS, PashovA, Monzavi-KarbassiB, MuraliR: Carbohydrate-mimetic peptides for pan anti-tumor responses. Front Immunol, 2014; 5:308.
37.
RagupathiG: Carbohydrate antigens as targets for active specific immunotherapy. Cancer Immunol Immunother, 1996; 43:152–157.