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Week’s Citation CIassIc~ ~
Wu I T & Kabat E A. An analysis of the sntjuences of the variable regions of Bence
Jones proteins and myeloma light chains and their implications for antibody
complenientarity. J. Exp. Med. 132:211-50, 1970; Kabat E A & Wu T T. Attempts
to locate complernentarity-deterrnining residues in the variable positions of light and
heavy chains. Ann, NY Acad. Sd. 190:382-93, 1971. lDepts. Microbiol., Neurol., and Human
Genet. and Develop. Coil. Physicians and Surgeons, Columbia Univ.. and Neurol. Inst.. Presbytenan Hosp., New
York; Depts. Phys. and Engineer. Sin.. Northwestern Univ., Evanston. IL; and Biomath. Div., Grad. Sch. Med.
Sd.. Cornell Univ.. and sloan-Kettering Inst.. New York, NY)
a quantitative measure, variability: Variability = Number of
These papers made use of available sequence data in 1970
and 1971 of variable regionsof light and heavy chains of ire- different amino acids at a given position/Frequency of the
most common amino acid at that position.
munoglobulins to predictthat the annbody-combining site was
formed by hypervariable regions and that they5contained the
When variability was plotted against amino acid position
forthe variable region of 71) human x and I, and 7 mouse u
complementarity determining residues. (The 5C1 indicates that
complete and partial light chains, the sequences of which
these papers have been cited in over 630 publications,(
were determined by many investigators, three distinct peaks
_____________________________________________
bracketed by invariant or nearly invariant residueswere seen
at positions 24 to 34, 50 to56, and 89 to 97, designated as
______
hypervariable. There were insertions numbered 27A to 27F
Complementarity-Determining
and others around position 95 now denoted by 95A to 9SF
Regions oj Antibodies
based on moredala. We predicted that these, together with
similar reejons in heavy chains, would form the antibody-com~
Tai Ic Wu
bining site. Nowwith many more sequences Irons various species of definedspecificities and from inbred lines, the peaks
Departments of Biochemistry, Molecular Biology,
and Cell Biology; Biomedical Engineering
in the variability plot have changed little.
and Engineering Sciences and Applied Mathematics
Th~i~iilowing
year, we made a similar plotfor the variable
Northwestern University
region of 37 complete and partial heavy chains, and again
three
distinct
peaks
were present as we had expected. Within
Evanston, IL 60201
a few years, our prediction was substantiated by three-dimenand
sional structures ofseveral hapten-binding Fal, fragments, light
Cancer Center
chain dimers, and one Fv fragment, and the sin hypervari.
Northwestern University Medical School
Chicago, IL Cr0611
able regions were named complementarity-determining regions (CDRs). More recently, a complex of lysozyme and an
September 26, 1989 antilysozyme Fab fragment was crystallized, and its three-dir
4
mensional structure was determined to 2.8 A resolution.
Fifteen amino acid residues from all six CDRsand Iwo frameWhen I was at Cornell University
Medical
College,
I
read
2
two very interesting articles” by th-inA. Kabat of Columbia work residues immediately adjacent tothe CDRs madeconUniversity Collegeof Physicians and Surgeons analyzing the tact with the lysozyme molecule. Two other lysozyme-antilysozyme complexes recognized differentepitopes and again
aminoacid distributions of tightchains of immunoglobulins.
Since I knew very little about immunology, I wrote to Elvin all six CURs were involved.~’Currently, all X-ray structures
of immunoglobulins have confirmed our prediction.
asking whether I could spend some time in hislaboratory.
After learning that I was also trained in engineering and
The fundamental contribution of our papers is the importantprediction that antibody-combining sites are formed by
applied mathematics andwas interested in mathematical bio.
physics, Elvin suggested instead that we should meet once the CDRs. It therefore becomes possible to design antibodies
with desired binding properties using recombinant DNA techa week to analyze the known sequence data on antibodies
in more detail, initially by writing them on long strips of paper niques. Several investigators have replaced CDRs of human
antibodies with those of mouse monoclonal antibodies with
and later by using computers. We reasoned that the variable
region of light chains ofimmunoglobulins could have random anticancer activities, In addition, variability plots have
5 also
been used to tryto locate COBs in 1-cell receptors, to tieamino acid substitutions just like other proteins. However,
fine residues that make contact with processed antigen and
at the antibody—combining sitet many more substitutions
would be needed to accommodate the vast number of dif. with 1-cell receptor
9 in the major hittocompatibility complex
ferent antigens. Such amino acid variaf ions were previously class I molecules and in the class I X-ray structure,’°and to
noted by Elvin as well as by Hilschmann and Craig, Putnam, identify hypes-variable regionsofvarious strains ofhuman imEdeinsass.- Fran8k.- Milstein and Pink,- and others. We defined munodeficiency viral envelope glycoproteins.”
-
I. Kabul K A. The paucity of species speciFic amino arid residues us the variable regions of human and mouse Bence Jones
proteins and its evolutionary and genetic implications. Pt-ne. Nat. Aced. Sin. USA 57:1345-9, 1967. (Cited 25 times.)
2.
. A comparison of invariant residues in the variable and constant regions of human a, bunsen )~
and mouse ii
Bence Jones proteins. Pt-ssc. Nat. Aced. Sin. USA 58:229-33, 1967. (Cited 15 times.)
3. Kabat E A, Wo T T, Reid-Miller M, Perry H M & Gottesoaan K S. Sequences of proteins ofimmunological interest.
Washington. DC: US Deparunent of Health and Human Services. Public Health Service, National tnststutes of Health,
1987. 804 p. (Cited 135 times.)
4. Mutt A Q, Mariuzze R A, Phillips S K V & PoIjak It J. Three dimensional structure of an antigen-antibody complex at
2.8 A resolution. Science 233:747-53, 1986. (Cited 180 times.)
5. Sheriff S, Sllvertnn K W, Padlan K A, Cohen C H, Smith-Cu S J, Fiozel B C & Davies I) R. Three-dimensional
structure of an antibody-antigen complex. Plr,c. Nat. Aced. Sd. USA 84:8075-9. 1987. (Cited 35 times.)
6. PadlanEA,SllvertonEW,SheriffS,CobenGH,Smitb-GUISJ&Das’iesDR. Strucmreofanantibody-antigen
complex: crystal structure of the HyHEL-lO Fab-lysozyme complex. Pine. Nat. Aca’S Sd. USA 86:5938-42, 989.
7. Jones P T, Dear P H, Foote J, Neuberger M S & Winter G. Replacing the complementarity-drtermining regions in a
human antibody with those from a mouse. Nalure 321:522-5, 1986. (Cited 45 times.)
8. Becker 0 M, Patten P. Chien ‘1, Yokota T, Rshhar Z, Giedlin M, Gascoigue N R J, Goodnow C, Wolf R, Arni K &
Davis M M. Variability and repertoire size of 1-cell receptor Via gene segments. Nature 317:430-4, 1985.
(Cited 60 times.)
9. Pus-ham P, Lonwn C E, Lawlor t) A, Ways.! P, Holmes N, Coppin H L, Salter It U, Wan A M & Room P U.
Nature of poly~~rnliisiis
its HLA-A. -B, and -C molecules. Pt-nc Nat. Acad~Sin. USA 85:4(8)3-9, 198K
W~J~rlthaiiFJ,S~perM A, Sam aoui
u~Wti~romingerJ L & Wiley D C Structure of the human class I
histocompatibility antigen HLA-A2. Nature 329:506-12, 1987. (Cited 225 times.)
II.
. The foreign antigen binding site and T cell recognition regions of class I itislocompatibility antigens. Nature
329:512-8, 1987. (Cited 195 times.)
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