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Recombinant Antibodies for Immunotherapy 1st Edition
Melvyn Little (Ed.) Digital Instant Download
Author(s): Melvyn Little (ed.)
ISBN(s): 9780511596377, 0511596375
Edition: 1st
File Details: PDF, 7.13 MB
Year: 2009
Language: english
RECOMBINANT ANTIBODIES FOR IMMUNOTHERAPY
Edited by
Melvyn Little
Affimed Therapeutics
CAMBRIDGE UNIVERSITY PRESS
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore,
São Paulo, Delhi, Dubai, Tokyo
Published in the United States of America by Cambridge University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9780521887328
© Cambridge University Press 2009
Every effort has been made in preparing this book to provide accurate and up-to-
date information that is in accord with accepted standards and practice at the time
of publication. Nevertheless, the authors, editors, and publisher can make no
warranties that the information contained herein is totally free from error, not least
because clinical standards are constantly changing through research and
regulation. The authors, editors, and publisher therefore disclaim all liability for
direct or consequential damages resulting from the use of material contained in
this book. Readers are strongly advised to pay careful attention to information
provided by the manufacturer of any drugs or equipment that they plan to use.
Contents
Preface xiii
v
vi Contents
Index 403
vii
viii Contributors
Jessica Snyder
Joe Ponte
Tolerx
Tolerx
Cambridge, Massachusetts, U.S.
Cambridge, Massachusetts, U.S.
Peter Sondermann
Beverly Potts
Glycart Biotechnology (Roche Group)
Raven Biotechnologies
Schlieren, Switzerland
San Francisco, California, U.S.
Philippe Stas
Patricia Rao Algonomics NV
formerly Tolerx Gent-Zwijnaarde, Belgium
Cambridge, Massachusetts, U.S.
now Synta Pharmaceutical Corp. Ross Stewart
Lexington, Massachusetts, U.S. MedImmune Ltd.
Cambridge, U.K.
Michael Rosenzweig
Tolerx Pablo Umaña
Cambridge, Massachusetts, U.S. Glycart Biotechnology (Roche Group)
Schlieren, Switzerland
Florian Rüker
Herman Waldmann
Department of Biotechnology
formerly Tolerx
University of Natural Resources
Cambridge, Massachusetts, U.S.
and Applied Life Sciences
now Sir William Dunn School of Pathology
Vienna, Austria
Oxford, U.K.
Dirk Saerens
Carl Webster
Laboratory of Cellular and Molecular
MedImmune Ltd.
Immunology
Cambridge, U.K.
Vrije Universiteit
and Department of Molecular and Cellular Gordana Wozniak-Knopp
Interaction Department of Biotechnology
VIB University of Natural Resources
Brussels, Belgium and Applied Life Sciences
Vienna, Austria
José W. Saldanha
Division of Mathematical Biology Peter Young
National Institute for Medical Research Raven Biotechnologies
Mill Hill, London, U.K. San Francisco, California, U.S.
Foreword
Antibodies were discovered in 1890 but remained on the periphery of the pharma-
ceutical industry for more than 100 years. Yet within the last 15 years, a succession of
antibodies has been approved for therapy by the United States Food and Drug
Administration (FDA). Unlike natural antibodies which are polyclonal and directed
against infectious disease, almost all those approved by the FDA are monoclonal
antibodies directed against human self-antigens and used for treatment of cancer
and diseases of the immune system.
Two major breakthroughs proved necessary to launch this antibody revolution.
The first breakthrough was rodent hybridoma technology in the 1970s. Antibodies
could now be made against single antigens in complex mixtures and used to identify
the molecular targets of disease. In some cases this allowed disease intervention by
blocking the antigen or by killing a class of cells (such as cancer cells) bearing the
antigen. However, hybridoma technology provided only part of the solution; the
rodent antibodies proved immunogenic and often did not trigger human effector
functions efficiently. The second breakthrough, in the 1990s, was protein engineer-
ing; its application allowed the creation of chimeric and humanized antibodies from
rodent monoclonal antibodies; not only were these less immunogenic than rodent
antibodies, but they more efficiently triggered human effector functions. These chi-
meric and humanized antibodies now account for the majority of the currently
approved therapeutic antibodies.
Nevertheless the field continued to embrace new technologies and to spawn new
approaches, most notably the development of genuine human antibodies in the
1990s. Human therapeutic antibodies were made by selection from highly diverse
antibody repertoires displayed on filamentous phage, and then from mice trans-
genic with human antibody genes. The pace of innovation continued in the new
millennium; antibodies were built from single domains, endowed with enhanced
effector functions or prolonged serum half-life, and even tailored to bind antigen via
engineered constant domains. Earlier approaches, for example those based on cyto-
toxic drugs or radio-immune conjugates, were also re-evaluated. In a field with few
clinically validated targets and a thicket of intellectual property, technological inno-
vation has offered freedom for new biotechnology companies to develop therapeu-
tics based on antibodies or antibody mimics.
Recombinant Antibodies for Immunotherapy, edited by Professor Melvyn Little,
covers both the fundamentals of the technology and the current state of its
xi
xii Foreword
The potential of antibodies as magic bullets for curing disease has excited the imag-
ination of medical researchers ever since this phrase was first coined by Paul Ehrlich
about a century ago. Seventy-five years after the publication of Ehrlich’s side-chain
theory to explain antibody-antigen reactions in 1900, Georges Köhler and César
Milstein invented a means of cloning antibodies with defined specificity that paved
the way for major advances in cell biological and clinical research. They were awarded
the Nobel Prize in Medicine in 1984 for this ground-breaking research. In 1986, the
first monoclonal antibody, the murine mAb OKT3 for preventing transplant rejection,
was approved for clinical use, and although many other murine mAbs were subse-
quently investigated as therapeutic agents, most of them had a disappointing clinical
profile largely due to their immunogenicity. This situation improved dramatically with
the advent of techniques to humanize existing mAbs, followed by technologies that
sought to imitate the generation of specific antibodies by the immune system in vitro.
For example, the expression of antibody fragments in E. coli using bacterial leader
sequences and the use of phage display and later ribosome display facilitated the
selection of specific human antibodies from extremely large libraries. The process
of somatic hypermutation to increase antibody affinity was mimicked by introducing
random mutations. Another major advance for obtaining human antibodies was the
creation of transgenic mice carrying a large part of the human antibody gene reper-
toire, which could be used to produce human antibodies by standard hybridoma
technology. The success of these novel technologies resulted in a first generation of
recombinant antibodies that now account for a large proportion of the market for
biopharmaceuticals, with annual growth rates of almost 40%.
Therapeutic antibodies for cancer rely to a large extent on the recruitment of other
elements in the immune system for their effect; very few of them function as magic
bullets in the sense of ‘‘target and destroy.’’ For example, although antibody binding
to a specific epitope of a cell surface receptor can directly induce strong apoptotic
signals, the effect is usually amplified by cross-linking of the antibody Fc domains
through binding to Fc receptors on immune effector cells such as macrophages and
natural killer cells. Concomitantly, the immune effector cells are activated by the
engagement of the Fc receptors, resulting in an attack on the cells to which they are
bound, a process known as antibody-dependent cell cytolysis (ADCC). The Fc
domains can also activate the complement system, causing complement-dependent
cytolysis (CDC). To what extent cell lysis is caused by direct binding and how much is
due to the recruitment of immune effector cells and complement is difficult to quan-
tify, especially in an in vivo system, and in many cases the mechanism of action of
xiii
xiv Preface
antitumor antibodies remains ill defined. For the action of most cytolytic antibodies,
all three mechanisms are probably involved to a lesser or greater extent. Furthermore,
recent findings suggest that ADCC also contributes to the efficacy of those antibodies
that were previously thought to cause tumor regression solely by blocking the ligand-
binding site of growth hormone receptors.
In the second generation of therapeutic recombinant antibodies now in various
stages of development, novel techniques and creative antibody engineering have
evolved to optimize pharmokinetic and pharmodynamic properties. For example,
the affinity of antibody Fc domains for their receptors on immune effector cells or
to complement has been improved by both random and targeted mutagenesis. Cell
lines have also been generated for altering the glycosyl side chains on the Fc domains
for better Fc-receptor binding. Algorithms and in vitro techniques have been devised
for predicting immunogenicity and selecting the best variants. In addition, the cyto-
toxic potential of antibodies and antibody fragments has been increased by arming
them with toxins, radionuclides, or immune effector molecules such as cytokines. A
large number of novel antibody formats ranging from single variable domains of
approximately 13kDa to full-length antibodies with multiple variable domains of
approximately 200kDa have been constructed to enable a variety of different func-
tions. For example, bispecific antibodies for recruiting T cells to lyse tumor cells have
been engineered without constant domains, thus reducing the risk of cytokine storms
due to extensive cross-linking with Fc receptors. Finally, a variety of novel protein
scaffolds are being investigated as alternatives to immunoglobulin fragments for the
generation of libraries of highly diverse binding molecules that could result in novel
therapeutic drugs. However, as nearly all of the alternative binding molecules are the
same size as or even smaller than single immunoglobulin domain antibodies, their
serum half-lives will probably have to be significantly extended using techniques such
as pegylation or fusion to serum proteins such as albumin.
All of the recombinant antibody technologies just described are covered by the 24
articles in this book, written by recognized experts in their field, many of whom have
pioneered important new techniques. Starting with a description of the technologies
used to generate recombinant antibodies, the following chapters provide a fairly
comprehensive overview, with examples and background information, on how anti-
body efficacy is being improved by decreasing immunogenicity, increasing effector
function through increased Fc-receptor binding, conjugating with cytolytic agents,
using novel formats and scaffolds with multiple valencies and specificities, and
increasing serum half-life. Several promising therapeutic approaches have been
included, such as a novel method for selecting antibodies that specifically lyse tumor
cells, the development of a recombinant antibody prodrug, and the use of novel
recombinant antibodies that target T cells for the treatment of autoimmune disease.
Last but not least, an attempt to forecast future developments in the field of ther-
apeutic recombinant antibodies has been made on the basis of an excellent market
analysis of this rapidly growing field.
M.L.
RECOMBINANT ANTIBODIES FOR IMMUNOTHERAPY
Figure 1.1. Schematic representations of mouse, humanized (chimeric, CDR-Grafted, reshaped, veneered/
resurfaced) and human antibodies. Blue, mouse content; red, human content; yellow, disulphide bridges; green,
carbohydrate moieties. VH, variable heavy domain; VL, variable light domain; CH1 to 3, constant heavy domains
1 to 3; CL, constant light domain; Fab, fragment antigen binding; Fc, fragment of crystallization; Fv, fragment
variable.
Figure 2.2. Top view of the HLA Class II DRB1*0101
binding groove, with a and b chains in blue and green,
respectively, and the bound peptide in orange (PDB-
code 1KLU).
Figure 11.5. Model of the interaction of glycosylated FccRIII with the Fc-fragment of IgG. Top: Clipping of the
crystal structure of non-glycosylated FccRIII expressed in E. coli (green) in complex with the Fc-fragment of
native (fucosylated) IgG (PDB code 1e4k, red and blue) as indicated in the inset. The glycans attached to the Fc
are shown as ball and sticks and colored accordingly. The fucose linked to the carbohydrate of the blue Fc-
fragment chain is highlighted in red. Bottom: Model of the interaction between a glycosylated FccRIII and the
(non-fucosylated) Fc-fragment of IgG. In this model, the carbohydrates attached at Asn-162 of FccRIII can
thoroughly interact with the non-fucosylated IgG. The figure was created using the program PYMOL (www
.delanoscientific.com).
4000
Tumor vol. mm3
3000
2000
1000
0
0 3 6 9 12 15 18 21 24 27
days
Figure 14.1. Efficacy of AS1409 in a PC3mm2 subcutaneous model.
Phosphate-buffered saline
huBC1-muIL-12 20lg 3 7 daily doses
huBC1 10lg & muIL-12 1.5lg 3 7 daily doses
muIL-12 1.5lg 3 7 daily doses
Figure 17.1. Ribbon presentation of the domains of an IgG1. Non-CDR loops are indicated in red, CDR loops in
green, and the beta sandwich core in blue. The structures are aligned such that the N-terminal ends are on the
top and the C-terminal ends are on the bottom.
Other documents randomly have
different content
He afterwards tried the Venus de Medici, but
that was a decided failure. He has been
favourably received by the patrons of British
Sports in the French capital, but it is feared he
cannot be presented at the Court of Louis
Philippe, in consequence of his having
neglected to present himself at the Drawing-
room of our lovely young Queen. In a visit to
the Jardin des Plantes, he thought he
recognised a young brother, but on closer
inspection he discovered it was only the
chimpanzee. He appears to be regarded with as
much curiosity in Paris as Soult was in London,
and expected the old Marshal would have given
him ‘a Wellington reception,’ but hitherto the
gallant veteran has not recognised him as ‘a
companion in arms.’ His presence has already
had an influence on the fashions, and
‘pantalons à la Burke’ have made their
appearance in the Palais Royal, while ‘gantelets
à la Deaf’un’ are noted as a novelty in Le
Courrier des Salons.”
We have already noticed in our memoir of
Bendigo that the Deaf’un did not return from his
continental trip until, after training Owen Swift, and
seconding him on the 5th of September, 1838, he
again sought the shores of England, lest he should
receive the “polite attentions” of the French
authorities for his share in that “scandal,” as the Paris
correspondent of “My Grandmother” styled it. The
staunchness of poor Burke’s “summer friends” was
now tested. They had withdrawn the £100 placed in
Jem Burn’s hands, but, after some negotiation, the
match was made, Burke posting £100 to Bendigo’s
£80, and on the 29th of February, 1839, the rivals
met. The full details of the Deaf’un’s defeat may be
read in pp. 16–22.
The reflection is here unavoidably thrust upon us,
that the so-called “friends” of an athlete, if they by
their own loose habits seduce him into similar
irregularities, are his worst enemies. What is sport to
them is ruin to him. Temperance, regularity of living,
open air exercise, and severe attention to the
wellbeing of every bodily function that goes to build
up health—the mens sana in corpore sano—can
never be neglected without ruinous consequences;
and thus fell the brave and imprudent Deaf’un, the
victim of the follies of those the world miscalled “his
betters.” A few quatrains on his downfall shall find a
place here.
THE LAMENT OF DEAF BURKE.
Well, ’tis strange, precious strange, arter what I have
done,
That in my late battle I shouldn’t have won;
I vow and protest, on the word of a bruiser,
I scarce can persuade myself yet I’m the loser.
I have always so well in the Ring gone to work,
That my backers proclaimed me “inwincible Burke;”
And then for a lad of my courage and game
To be floored by a novice—by Jove! ’tis a shame.
I hang down my head, quite dismay’d and perplex’d.
And when folks ax me questions, of course, I am
wex’d,
For, instead of consoling me under my loss,
They insiniwate plainly the thing was a cross.
They swear, for a man who has stood so much fight,
To be whopp’d in ten rounds was impossible quite:
That I couldn’t be he, it was plain to discern,
Wot floor’d Carter and Crawley, O’Connell and Byrne.
They vow of their bets upon me they’ve been robb’d,
That I show’d no good point, but stood still to be
jobb’d,
That no punishment sharp was produced by my
blows,
And Bendy did with me whatever he chose.
Hard words for the Deaf’un, and cruel the sting,
Hard words for the Deaf un, and cruel the sting,
To one who ne’er acted amiss in the Ring—
To him who was always alive to a mill,
And in thirteen prize-battles was conqueror still.
I boldly appeal to my slanderers whether
I was ever the covey to show the white feather?
And Bendigo’s conduct I cannot think right,
When he stripp’d me of something that lost me the
fight.
That he acted unfairly I do not advance—
He was perfectly right not to part with a chance;
Still I say, but for this, whosoever may scoff,
He would not have easily polished me off.
And may I again never put on a glove,
If once more I don’t fight him for money or love;
And my stick I will cut in the Prize Ring, by Jove!
Ere the belt shall be worn by a Nottingham cove.
And shall poor Deaf Burke be consign’d to the
shade?
No, tho’ I’m defeated I am not dismay’d,
And in a fresh contest I’ll do what I can,
To take the conceit from this bounceable man.
When victory smiles on a pugilist’s front,
He has lots of supporters and plenty of blunt;
But if luck turns against him, my eyes! how they
rave
rave,
And stamp him a cross cove—a thundering knave!
Into me some choice worthies keep pitching it home,
For sporting the statutes of Greece and of Rome;
Is it fair, I would ax, to inflict this here slap,
Because I’m a sort of a classical chap?
And some swear ’tis time I was laid on the shelf,
For I grows ’ristocratic—too sweet on myself;
Now I wenture most humbly to make an appeal,
If I’m to be blam’d for behaving genteel?
In France and New York I have sported my tanners,
And no wonder a polish I have got on my manners;
Now, I begs to inquire whether winner or loser,
Must a man be a blackguard because he’s a bruiser?
No, to tip the purlite I will still do my best,
For everything wulgar I scorn and detest;
My pipe I’ve discarded like most other stars,
And now I smoke nowt but Hawanna cigars.
And I dare say some folks may consider it strange,
That I’m courting the Muses by way of a change,
And thus in Bell’s Life to my feelings give went,
In a copy of werses I’ve called “The Lament.”
Be this as it may, here I’m ready and willing
This Bendy again to encounter at milling,
And perhaps if I once get him into a line
And perhaps if I once get him into a line,
Tho’ the first chance was his’n, the next may be
mine.
That “next chance,” as Edgar Poe’s raven said,
“never, never, never more” came to the turn of the
Deaf’un, so far as regarded a meeting with Bendy,
although he issued sundry invitations and offers. In
March, 1840, occurred the accident to Bendigo,
narrated at page 25, which struck the Nottingham
hero from the list of “wranglers” for the
Championship, and hereupon Burke again came to
the front with a challenge. This was quickly
responded to by Nick Ward, the younger brother of
the renowned Jem. The match was made for the
modest sum of £50 a side, and the day fixed for
Tuesday, the 22nd September, 1840. The battle,
which took place at Lillingstone Level, Oxfordshire,
will be found in detail in the Life of Nick Ward,
Chapter V. of the present volume.
Poor Burke’s day was gone by; unconquered in
heart, his impaired physical powers failed him, and
he fell before youth, activity, skill, and length. As we
have mentioned in our memoir of Nick Ward that the
stakeholder received notice of action for the stakes,
it is but just to give the following vindication of the
Deaf’un’s conduct as reported in a contemporary
journal:—
“The Deaf’un Himself Again!—The Deaf’un took
a benefit at the Bloomsbury Assembly Rooms
on Tuesday evening, and, notwithstanding his
late defeat, found a goodly number of friends,
and ‘a strong turn’ in the financial department.
The sets-to, although many of them between
commoners, were amusing and effective, and
conducted with great spirit and vigour. Among
the most popular was that between Owen Swift
and Maley, in which the quickness and scientific
deliveries of the former were happily illustrated.
At the conclusion the Deaf’un mounted the
stage to ‘wind-up,’ but unfortunately, Caunt
having forfeited his promise to appear, he was
only opposed to a new beginner called ‘The
Cumberland Youth,’ whose inexperience left the
star of the night nothing to do but flap him at
pleasure. The Deaf’un, after smoothing down
his bristles with his dexter digits, and clearing
his throat by sundry ‘hems,’ delivered himself of
the following oration, which we took down as
nearly as could be verbatim. ’Gemmen—I have
dis here to say. I’m werry sory as Caunt has not
come to sets-to wid me according to his
promises, for he gave me his words of honours
as he would attend; but dats de way wid dese
here mens—when dey gets to the top of de
trees, dey do nothing to help a poor fellow as is
down; but dey had better minds what dey are
abouts, or they’ll be as bad as Jack Scroggins,
and look for a tanners when they can’t find it.
Gemmen—I mean to say as I do not thinks as I
was fairly beat by Bendigo, and I am prouds to
say as I am not widout friends what tink de
same, and as are ready to back me for a cool
hundreds against him, or Nick Wards, or Jem
Bailey. Bendigo is wery bounceable now, as he
says he has licked me; but I says he took an
unfair advantage in regard of my belt; but dats
neither one ting nor toder; and if he has
friends, if he’s a man, he’ll give me anoder
chance, and till he does, I shall always thinks as
he has won de belts widout any right to it. I
went to Sheffields and Nottinghams to make a
match wid him, and now let him show equal
pluck and come to London to make a match wid
me—my pewters is always ready (applause).
Dat’s all I’ve got to say. Gemmen, I thank my
friends and patrons for coming here to-night
(coughing); but I’ve got something here
(pointing to his throat, and the poor fellow
appeared overflowing with gratitude) which
won’t let me say no mores.’—It is not very
creditable to the élite of the Fancy to have
abstained from setting-to for the unfortunate
fellow; for, although his ignorance may have led
him to assume too much, the motto of all
professed pugilists should be ‘forget and
forgive;’ and ‘if a man’s in distress, like a man
to relieve him.’”
In the years 1841–2, the magistracy and police,
stimulated into abnormal activity by a sort of clerical
crusade against the Ring “and all its works,” set the
powers of the law in motion against pugilists and
their patrons, and “all persons aiding and abetting in
riotous and tumultuous assemblages calculated to
produce a breach of the peace,” by issuing warrants,
holding them to bail, and indicting them at the
quarter sessions of the county wherein the same
took place. Among the zealots of this Puritanical
campaign against the amusements and relaxations of
the people, the Rev. Joshua Cautley, curate of
Broughton, in Bedfordshire, distinguished himself
with the fervour of Ralpho, the squire of Sir
Hudibras; though he, fortunately, escaped the
cudgellings, rotten eggs, and stocks, which in
rougher times befell his prototype. In an evil hour
the Deaf’un came in contact with this clerical
suppressor of “anti-knife” congregations, under the
serio-comic circumstances we are about to narrate.
On the 9th of February, 1841, at Holcut, in
Bedfordshire, an orderly assemblage surrounded a
well-arranged inner-and-outer ring, within the latter
of which Ned Adams, of London, and Dick Cain, of
Leicester, were contending. At a critical period of the
battle, the curate of Broughton, the Rev. Joshua
Cautley, who was not, as all the “rurals” surrounding
the ring well knew, either a magistrate in the
commission of the peace, or in any way legally
authorised to interfere, appeared at the ring-side in
an excess of peace-preserving furor, and not only
attempted to take Adams into custody (without any
warrant), but cut the ropes with a knife, and
behaved otherwise in an outrageous manner. He was
afterwards aided by a police constable (John
M’Hugh), and by the arrival of the Rev. Edward
Orlebar Smith, a Justice of the Peace for
Bedfordshire, previous to whose appearance on the
scene certain of the country people present had
certainly ejected Parson Cautley from the ring. The
Rev. Justice of the Peace, as it appears, then put his
fellow clergyman and himself on the right side of the
law by reading—at a distance, and amidst immense
confusion and the continuance of the battle—the Riot
Act. The result of all this was that the zealous Parson
Cautley procured, upon affidavit sworn by himself,
the constable, and the Rev. Mr. Smith, the indictment
of thirteen persons (six of them being his own
neighbours) at the ensuing Bedford Quarter
Sessions. The pugilists indicted were James Burke,
Owen Swift, Edward Adams, and Richard Cain,
Thomas Brown (the respected landlord of the
“Swan,” at Newport Pagnell, who was there in charge
of his post-horses and four-in-hand), Messrs. Mark
Cross, William Maley (a solicitor), Joseph Goodwin,
George Durham, Edward Dawkes, James Morris the
younger, Martin Hughes (who died during the
proceedings), and Richard Walter Chetwynd,
Viscount Chetwynd, Baron Rathdowne. The
indictment charged, in its first count, “that they, the
defendants aforesaid, on the 9th day of February,
1841, in the parish of Holcut, in the county of
Bedford, did then and there, together with other evil-
disposed persons, whose names are unknown to the
jurors aforesaid, unlawfully, riotously, and
tumultuously assault Edward Orlebar Smith, clerk,
one of the Justices of the Peace for the said County,
and John M’Hugh, one of the constables of the Peace
for the said County, and, then and there, did, in
contempt of our said Lady the Queen and her laws,
to the great terror, alarm, and disturbance of all the
liege subjects of our said Lady the Queen
thereabouts inhabiting and residing and being,
passing and repassing, to the great damage of the
said Edward Orlebar Smith and John M’Hugh, and
against the peace of our said Lady the Queen her
crown and dignity.” The second count in this
formidable document, repeating the names and
verbiage, included the same charges against the
defendants for riot and assault on the person of the
Rev. Joshua Cautley. The third count varied by
specifying James Burke as the assailant of the Rev.
Edward Orlebar Smith (whom he never touched in
any way). The 4th, 5th, 6th, and 7th counts merely
varied in the names of the parties assaulted, by
substituting “Smith” for “M’Hugh,” and “Cautley” for
“Smith,” as the persons on whom “with force and
arms,” the same defendants “did then and there
beat, wound, and ill-treat, and do other wrong, to
the great damage of the said E. O. Smith,” &c., &c.,
“and against the peace of our said Lady the Queen
her crown and dignity.”
Any one not used to the formal wording of legal
documents may well share the astonishment of the
Deaf’un when this astounding rigmarole, being
furnished to his legal advisers (Mr. Vincent Dowling
and Mr. Serjeant Dowling), was read and explained
to him. His truthful and indignant denials of all the
serious delinquencies laid to his charge in this
farrago of legal fictions were most amusing. Perhaps
the way in which these were thrown into rhyme, by
what old Jacob Tonson, the bookseller, used to call “a
competent pen,” will convey some idea of the
Deaf’un’s objections and denial of the charges:—
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