Expert Opinion on Investigational Drugs

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The long-awaited magic bullets: therapeutic

human monoclonal antibodies from transgenic
mice

Aya Jakobovits

To cite this article: Aya Jakobovits (1998) The long-awaited magic bullets: therapeutic human
monoclonal antibodies from transgenic mice, Expert Opinion on Investigational Drugs, 7:4,
607-614, DOI: 10.1517/13543784.7.4.607

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 Expert Opinion on Investigational Drugs
Jakobovits
Therapeutic human monoclonal antibodies from transgenic mice
The long-awaited magic bullets:
therapeutic human monoclonal
antibodies from transgenic mice
Aya Jakobovits
http://www.ashley-pub.com
Abgenix, Inc., 7601 Dumbarton Circle, Fremont, CA 94555, USA

Update The ability to produce a diverse repertoire of fully human monoclonal

antibodies (mAbs) may have significant applications to human therapy.
1. Introduction This update describes the creation of a novel tool for the production of
2. XenoMouse–mouse strains therapeutic human mAbs: a mouse strain engineered to produce a large
engineered with human Ig range of human antibodies in the absence of mouse antibodies. This strain,
loci XenoMouse, has been generated by the introduction of large segments of
human immunoglobulin loci, containing the majority of the human
3. Production of fully human antibody gene repertoire, into mice deficient in mouse antibody produc-
antibodies by XenoMouse tion. The mice produce a diverse array of authentic fully human IgGκ
B cells antibodies. Upon immunisation with multiple human antigens the mice
generate large panels of high affinity, antigen-specific fully human mAbs
4. Production of high affinity
with therapeutic activities. XenoMouse-derived hybridomas were shown to
antigen-specific human
be stable, producing significant levels of human mAbs. XenoMouse
mAbs
technology represents an efficient and reliable tool for the production of
5. XenoMouse technology - therapeutic human mAbs, which can accelerate the evaluation and valida-
one step tool for tion of antibody therapy in human disease.
generating and
Keywords: human antibodies, human monoclonal antibodies, immunoglobulin
manufacturing therapeutic
genes, therapeutic antibodies, transgenic mice
human mAbs
Bibliography Exp. Opin. Invest. Drugs (1998) 7(4):607-614

1. Introduction
With 80 monoclonal antibodies (mAbs) in development worldwide, about
20 in clinical trials, 2 approved in 1997 and more to be submitted for FDA
approval in 1998, it seems that the premise of mAbs as ‘magic bullets’ is
finally about to be fulfilled. This can, in part, be attributed to the better
understanding of the therapeutic indications that suit antibody therapy, the
improved design and evaluation of clinical protocols using mAbs and the
progress in antibody manufacturing. More importantly, this advance is
largely due to the technical progress made with producing safer, and more
stable and efficacious mAbs, primarily by making the antibodies as ‘human’
as possible.
Mouse antibody sequences have been shown to be immunogenic in
humans, inducing a human antimouse antibody (HAMA) response that
leads to rapid clearance of the administered antibodies and a reduction in
their efficacy and safety. Such limitations should be overcome by the
availability of fully human monoclonal antibodies, which are expected to
minimise immunogenic and allergic responses. The use of fully human
antibodies may be critical in the treatment of chronic and recurring human
diseases that require repeated antibody administration, such as cancer,
607
1998 © Ashley Publications Ltd. ISSN 1354-3784
608 Therapeutic human monoclonal antibodies from transgenic mice

Figure 1: A schematic representation of the strategy used to generate XenoMouse II strains producing human antibodies in the place of
mouse antibodies. Mouse heavy and k light chain genes were inactivated in ES cells by gene-targeting technology. The targeted ES
cells were utilised to generate mice, homozygous for each of the heavy and k chain deletions, in which murine antibody production is
disrupted. Human heavy and k chain loci, contained on YACs, were introduced into ES cells and the modified ES cells were used to
generate mice containing integrated human Ig YACs and producing fully human antibodies in the presence of mouse antibodies.
Breeding these mice with Ig-inactivated mice generated XenoMouse II strains, producing human antibodies in the absence of mouse
antibodies.
ES: Embryonic Stem; YAC: Yeast artificial chromosome.

autoimmunity and inflammation. In addition, fully
human mAbs will permit the treatment of immuno-
competent patients who can mount a normal immune
response to the foreign mouse sequences.
Fully or partially human mAbs can be generated by
employing a variety of techniques, each having their
own limitations. Application of the hybridoma
methodology to generate antigen-specific human
© Ashley Publications Ltd. All rights reserved.
mAbs from human B-cells is limited by the scarcity of
human B-cells expressing antibodies of the desired
antigen specificity and by difficulty in their immortali-
sation [1]. The replacement of parts of the mouse
mAbs with human sequences to generate chimeric [2],
or humanised antibodies [3], with reduced immuno-
genicity, requires case-by-case design and
engineering for each individual antibody. Further-
more, these mAbs still retain some mouse sequences.
Exp. Opin. Invest. Drugs (1998) 7(4)

The generation of large human Ig gene combinatorial
libraries has opened the way for the cloning of
antigen-specific fully human antibodies [4,5].
However, in many cases, the use of this technology to
generate high affinity human antibodies, particularly
to human antigens, requires extensive in vitro
manipulation.
To overcome the difficulties associated with the in
vitro production of human antibodies of therapeutic
value we engineered mice with human antibody
genes to generate and select high affinity human
antibodies and utilised the mouse hybridoma
technology to derive mAbs from immunised mice.
These mice should lack immunological tolerance to
and should therefore readily yield antibodies to
human proteins. It should be possible to use these
mice as valuable sources of fully human mAbs with
high affinity and specificity directed against a broad-
spectrum of antigens. The desired mouse strains
should be deficient in mouse antibody production
and engineered with unrearranged human Ig loci to
reconstitute a functional humoral immune system and
to produce authentic fully human antibodies.
However, the success of such an approach relies on
the ability to reproduce the human antibody response
in mice by providing the mice with the large variable
gene diversity required to generate high affinity
antibodies to any desired antigen.
This update will describe the properties of the
XenoMouse technology and its use in the production
of high affinity human mAbs to multiple clinically-
relevant antigens. The rapid and easy generation of
antigen-specific human mAbs should accelerate the
production of fully human antibodies of therapeutic
value and their clinical development.
2.XenoMouse - mouse strains engineered
with human Ig loci
The reproduction of the human humoral immune
system in mice has been achieved by two major
genetic manipulations of the mouse genome: the
inactivation of mouse Ig genes and the stable
introduction of cloned human Ig loci (Figure 1 [ 6,7]).
Both genetic modifications were carried out in mouse
embryonic stem (ES) cells, which allowed the
transmission of these genetic modifications into the
mouse germline.
© Ashley Publications Ltd. All rights reserved.
Jakobovits 609
Mouse heavy and kappa (κ) light chain loci were
inactivated by gene targeted deletions of crucial
cis-acting sequences involved in the process of mouse
Ig gene rearrangement and expression, JH and Cκ,
respectively [6-8]. In mice homozygous for the inacti-
vated alleles, the production of antibodies and,
therefore, B-cell development were completely
arrested [6,7]. However, these mice retained intact
machinery for antibody rearrangement and expres-
sion and therefore their humoral immune system
could be reconstituted by unrearranged Ig loci. Large,
germline configuration fragments of the human heavy
and κ chain loci were introduced into this mouse
Ig-inactivated background in order to preserve the
variable gene diversity and to maintain the regulatory
elements that control antibody recombination,
expression and maturation. The human heavy and κ
light chain loci, each over 1.5 mb in size, consist of the
variable segments encoding the Variable (95 VH , 76
Vκ genes), Diversity (30 DH genes) and Joining (6 JH, 5
Jκ genes) domains, the segments that encode the
constant (C) domains, and the interspersed regulatory
elements that control antibody expression, allelic
exclusion, class switching and affinity maturation
[9,10]. Therefore, reproduction of the human antibody
response in mice required the cloning of mb-sized
fragments from the human heavy and κ light chain
loci and their introduction, in intact form, into the
mouse germline. This was facilitated by the Yeast
Artificial Chromosome (YAC) technology which
permitted the isolation and genetic manipulation of
mb-sized DNA fragments and allowed their introduc-
tion into the mouse genome by the fusion of
YAC-containing yeast spheroplasts and ES cells
[6,7,11]. By cloning and recombining DNA fragments
that span the majority of the human heavy chain
locus, we reconstructed a 970 kb YAC encompassing
in germline configuration, the Cµ and Cδ constant
regions, all six functional JH genes, all 30 D segments
and about 66 different consecutive VH genes from
VH6-1 to VH3-65, representing 80% of the human VH
gene repertoire (Figure 2A, [7]). The region 3′ of the
Cδ region was retrofitted with either human γ1, γ2 or
γ4 constant region, in conjunction with the mouse 3′
enhancer, to generate 3 mb-sized heavy chain yH2
YACs, each equipped with a different human γ
constant gene (G1, G2 and G4, respectively). The
reconstructed 800 kb yK2 YAC contained the human κ
chain proximal locus, including the kappa deleting
element, the kappa 3′ and intronic enhancers, Cκ, Jκ
and the majority of the proximal variable region
Exp. Opin. Invest. Drugs (1998) 7(4)
© Ashley Publications Ltd. All rights reserved.

610 Therapeutic human monoclonal antibodies from transgenic mice

Figure 2: Schematic representation of human heavy and k chain YACs present in XenoMouse II strains. The structure of human Ig YACs with respect to the human Ig loci and
their sizes are indicated (not shown to scale). The YAC vector elements: telomere >, centromere !, and mammalian (HPRT, Neo) on the YAC vector arms are indicated. VH
segments are classified as genes with open reading frame !, pseudogenes 1, and non-rearranged genes with open reading frames that can also be classified as pseudogenes (gray
circle). Vk segments are classified as genes with open reading frames !, and pseudogenes 1. The V genes found so far to be utilised by the mice are marked (*).

A. Human heavy chain YAC

~66 V H genes D J H Cµ Cδ Cγ m3’E Neo
yH2 (1020 kb)

5’ 3’
7-77

3-66

4-55

2-26

1-17
7-81
4-80
3-79
5-78

3-76
3-75
3-74
3-73
3-72
3-71
2-70
1-69
1-68
1-67

3-65
3-64
3-63
3-62
4-61
3-60
4-59
1-58
3-57
7-56

3-54
3-53
3-52
5-51
3-50
3-49
3-48
3-47
1-46
1-45
3-44
3-43
3-42
3-41
7-40
4-39
3-38
3-37
3-36
3-35
4-34
3-33
3-32
4-31

3-30
3-29
4-28
7-27

3-25
1-24
3-23
3-22
3-21
3-20
3-19
1-18

3-16
3-15
1-14
3-13
1-12
3-11
2-10
D J H Cµ Cδ

3-9
1-8
3-7
3-6
2-5
4-4
1-3
1-2
6-1
* * * * * * * ** * * * * * * * * * * * * *

B. Human κ light chain YAC

L5

B2
B3
B1
~32 V κ genes Jκ Cκ Kde Neo

~
~
yK2 (800 kb)

~
O11
O12
O13
O14
O15
O16
O17
O18
A15
A16
A17
A18
A19
A20
A21
A22
A23
A24
A25
A26
A27
A28
A29
A30

L10
L11
L12
L13
3’ 5’

B1
B2
B3
L1
L2
L3
L4
L5
L6
L7
L8
L9
Exp. Opin. Invest. Drugs (1998) 7(4)

Jκ Cκ Kde

* *OP * * * AP ** *** * LP B *
 Jakobovits 611

Table 1: Characterisation of XenoMouse II-derived human mAbs specific to human IL-8 and EGFr. The variable gene
composition of the human mAbs and their affinity constants to their respective antigen, measured on BIAcore, are shown.
EGFr: Epidermal growth factor receptor.

Antigen Human mAb Antibody composition Affinity

measurement
IgG2k VH D JH Vk Jk KD (M)
Human IL-8 D1.1 4 - 34 21 - 10rc J H3 018 Jk3 3.7 x 10-10
K2.2 4 - 34 K1 JH4 B3 Jk3 2.5 x 10-10
K4.2 3 - 30 Ir3rc J H4 018 Jk4 1.6 x 10-10
K4.3 5 - 51 A1/A3 JH4 012 Jk4 2.2 x 10-10
Human EGFr E1.1 4 - 31 2 JH5 018 Jk4 3.5 x 10-10
E2.4 4 - 31 A1/A4 JH3 018 Jk4 3.5 x 10-11
E2.5 4 - 31 XP1 JH4 018 Jk2 8.4 x 10-11
E2.11 4 - 61 XP1 JH4 018 Jk4 2.7 x 10-10

(Figure 2B, [7]), with 32 Vκ, representing about 75%
of the unique Vκ gene repertoire.
Using these YACs we generated three XenoMouse II
strains, all homozygous for the inactivated mouse
heavy and κ chain loci and bearing the yK2 YAC in
conjunction with one of the three heavy chain yH2
YACs. Each of these XenoMouse strains (G1, G2, G4)
produces fully human antibodies with different
isotype-IgG1κ, IgG2κ, or IgG4κ, respectively, allowing
the efficient production of human mAbs with the
desired effector function best fitting the disease
indication.
3. Production of fully human antibodies by
XenoMouse B-cells
Analysis of Xenomouse II lymphoid organs and serum
demonstrated that the human Ig YACs were fully
compatible with the mouse machinery for antibody
recombination and expression [7]. They restored
normal B-cell development and induced the produc-
tion of high levels of fully IgM and IgG human
antibodies, both before and after immunisation. The
YACs restored mature B-cell populations in
XenoMouse bone marrow, peripheral blood, spleen
and lymph nodes at levels comparable to those of
wild-type. The majority of XenoMouse B-cells (95%)
expressed exclusively human κ chain, whereas only
about 5% expressed the functional mouse lambda (λ)
chain, indicating the ability of the human κ chain
locus to substitute for the inactivated mouse κ and to
obtain mouse wild-type-like κ/λ distribution ratio.
Therefore, most of the B-cells in XenoMouse strains
exclusively express and secrete fully human
antibodies at levels comparable to mouse antibodies
secreted by genotype-matched wild-type mice kept
under similar pathogen-free conditions (about 800
µg/ml). The significant levels of human γ in all
XenoMouse strains, which increased to 2.5 mg/ml
upon immunisation, indicated an efficient class
switching in XenoMouse II strains.
Analysis of heavy and κ chain transcripts, isolated
from XenoMouse spleen, lymph nodes or hybridomas
revealed a broad non-position biased utilisation of V,
D and J segments contained in the YACs, which is
reminiscent of adult human B-cells [6,7]. The analysis
thus far has detected the utilisation of 22/34 known
functional VH genes present on yH2 and 12/18
functional Vκ genes on yK2 (Figure 2). The variable
genes utilised are widely distributed over the entire
span of both YACs, indicating that all the variable
regions present on yH2 and yK2 YACs are accessible
to the mouse system for antibody rearrangement and
are being utilised. VHDJH recombination products
were linked properly to Cµ or Cγ and the VκJκ
sequences were linked to the Cκ region. The comple-
mentarity determining regions (CDR3s) were of 8 - 19
and 9 - 10 amino acids in length, for the heavy and κ
chains, respectively, comparable to the CDR3s
observed in adult human B-cells and much longer
than the average mouse CDR3s again consistent with
the structure of adult human-like antibodies [6,7].
Sequence analysis of the heavy and κ chain transcripts
from the generated human mAbs indicated that they
were each derived from a distinct recombination
event (Table 1) and that an extensive somatic
hypermutation process occurs in XenoMouse II [7].

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1998) 7(4)
612 Therapeutic human monoclonal antibodies from transgenic mice
Therefore, all three critical processes for antibody
diversification, maturation and selection-VDJ
recombination, junctional diversity and somatic
hypermutation, are fully functional in XenoMouse
strains. The recapitulation of authentic human
antibody production in Xenomouse II indicated that
the sequences on yH2 and yK2 YACs direct the mouse
machinery to produce an adult human-like antibody
repertoire in mice.
4.Production of high affinity
antigen-specific human mAbs
The exploitation of the large human repertoire in
XenoMouse II for the generation of a diverse human
antibody response was manifested by the production
of high affinity human antibodies to multiple antigens,
including human antigens. Immunisation of
XenoMice and derivation of hybridomas from spleen
or lymph nodes were carried out by the standard
protocols developed for wild-type mice. When
XenoMice II were challenged with different human
antigens such as IL-8, Groα, L-selectin, EGF receptor
(EGFr), IL-6 or tumour necrosis factor-α (TNF-α), a
strong (1:106 titre) antigen-specific human antibody
(IgGκ) response was detected, and hybridomas
secreting antigen-specific human mAbs were readily
selected. The immunogens used were either soluble
proteins (such as IL-8, IL-6, Groα, and TNF-α) or
expressed on the surface of cells (EGFr and L-selectin
on A431 and 300.19 cells, respectively). A large panel
of 10 - 50 hybridomas secreting antigen-specific
human IgGκ antibodies was obtained for all the
antigens tested, from which high affinity mAbs with
the desired specificity and biological activity could be
selected. Characterisation of purified XenoMouse-
derived human mAbs on protein gels, under
non-reduced conditions, revealed the expected
apparent molecular weight of 150 - 170 kDa for IgGκ,
and reduced conditions showed a 53 - 54 kDa for the
heavy and 31 - 32 kDa for the light chain. Human
mAbs with subnanomolar affinity values (10-9 - 10-11
M) were readily identified (Table 1). The consistency
between the affinity measurements performed by
solid phase with whole antibodies, or their derived
Fab fragments and those carried out in solution,
validated the measured dissociation constants as true
affinity rather than avidity values [7].
From each panel of antigen-specific hybridomas, a
subset secreting human mAb with neutralising activity
© Ashley Publications Ltd. All rights reserved.
was selected. The antibodies to human IL-8 reacted
only with IL-8 and not with related cytokines, such as
MIP-1α, GROα, β and γ, ENA-78, MCP-1, or RANTES.
All antibodies inhibit IL-8 binding to human neutro-
phils and were able to block neutrophil responses to
IL-8, including up-regulation of the integrin
CD11b/CD18, elastase release, chemotaxis and
calcium mobilisation. The antibodies tested were
capable of inhibiting IL-8 and LPS-induced skin
inflammation in rabbits, preventing psoriatic plaque
formation in SCID mouse models and inhibiting
IL-8-induced angiogenesis in rat corneas [manuscript
in preparation]. The antibodies to TNF-α blocked the
cytokine binding to its receptors on U937 cells. The
antibodies to EGFr inhibited EGF and TGF-α binding
to EGFr on human carcinoma cell lines and
EGF-mediated cell proliferation in vitro. In xenograft
mouse models, the tested antibodies prevented
tumour formation and completely eradicated
established tumours [manuscript in preparation].
These results demonstrated the ability of XenoMouse
to generate panels of high affinity, antigen-specific
fully human mAbs to multiple human antigen targets.
The high potency of the generated antibodies in
blocking the biological effects of their respective
antigens on human cells indicated their potential
therapeutic use.
5.XenoMouse technology - one step tool for
generating and manufacturing therapeutic
human mAbs
The described Xenomouse II strains validate the
promise of mice engineered with large human Ig
fragments as a useful tool to produce a diverse
repertoire of fully human antibodies with high affinity
and specificity for their target antigens. The large
antibody repertoire in XenoMouse II is properly
exploited by the mouse machinery for antibody
diversification and selection, yielding a human
antibody response that is comparable in its diversity
and functionality to that observed in adult humans.
The spectrum of antigens against which XenoMouse
strains produced high affinity antibodies, and the ease
with which these antibodies were generated, can
largely be attributed to the large human antibody gene
repertoire on the human Ig YACs. XenoMouse-
derived mAbs were shown to be equivalent in their
affinity, specificity, and biological functions to those
generated by wild-type mice. The affinity values
Exp. Opin. Invest. Drugs (1998) 7(4)

Figure 3: XenoMouse technology - one step tool for the production and manufacture of therapeutic, fully human mAbs.
Immunisation of XenoMouse strains
Antibody-producing B cells
drawn from immunised XenoMice
Myeloma cells
Fusion of antibody-producing B cells
and myeloma cells
obtained for XenoMouse-derived antibodies are the
highest to be reported for human antibodies against
human antigens, produced from either engineered
mice [12], or directly from naïve combinatorial
libraries [13]. The process of identifying antigen-
specific human mAbs with high affinity from
XenoMouse takes about 3 months. The rapidity and
reproducibility with which Xenomouse II yields
panels of antigen-specific fully human mAbs, are
some of the advantages that this approach offers over
other technologies for human antibody production.
Humanisation of mouse mAbs is time consuming,
labour intensive and requires confirmation of
functionality of the modified antibody. Phage
display-derived antibodies often require intensive
efforts to enhance their affinity and to engineer them
into intact antibodies. The ability of XenoMouse to
readily produce high affinity human mAbs with any
desired specificity and with any of the three desired
human isotypes eliminates any need for antibody in
vitro engineering and thus reduces the time to initiate
product development by 6 - 18 months as compared
to other technologies. In addition, stable
XenoMouse-derived hybridomas, producing signifi-
cant levels of human mAbs (200 - 400 µg/ml), can be
used as manufacturing cell lines, thus avoiding the
need to clone and express the antibody genes in other
© Ashley Publications Ltd. All rights reserved.
Jakobovits 613
Fully human mAbs
mAb purification
Standard cell-based manufacturing
Mouse hybridoma cell line secreting
antigen-specific human mAb
cell lines (Figure 3). The XenoMouse technology
represents a one step tool for the production of
therapeutic human mAbs, permitting a substantial
saving in time and cost at the early stages of antibody
development and thus accelerating the evaluation and
validation of antibody therapy in human diseases.
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Aya Jakobovits, Director, Discovery Research
Abgenix, Inc., 7601 Dumbarton Circle, Fremont, CA 94555, USA
(Tel: +1 510 608 6500; Fax: +1 510 608 6511;
Email: jakobovits_a@abgenix.com)
Exp. Opin. Invest. Drugs (1998) 7(4)