Extract
Note: Please read the complete
full text with Figures and Tables at
Introduction
Monoclonal antibodies (mAb) are unique and versatile
molecules that have been found applications in
research, diagnosis, and in the treatment of multiple diseases,
including cancer. The advent of hybridoma technology for mAb
production in 1975[1] was a breakthrough in the field of
biomedicine; 30 years later, a plethora of biotech companies
produces thousands of mAb, and at least 17 of them have
FDA (US Food and Drug Administration) approval for
therapeutic use in patients, with hundreds of them still in the
pipeline.
However promising their future is, the development of
therapeutic mAb suffered a number of serious drawbacks,
which considerably reduced faith in their clinical applicability.
These disappointments were caused by their inability to
trigger human effector functions, and because repeated
administration provoked an immune response against murine
antibody (Ab) domains (HAMA, human anti-murine
Abs)[2]. Recently developed technologies (phage display and transgenic mice) allow the selection and identification of fully
human Ab, as well as the improvement of Ab
affinity[3]. The ability to generate human mAb achieved 2 important goals: it overcame most host anti-Ab responses, and it extended the half-life of the reagent to something closer to that of normal IgG. As a result of these advances, mAb are starting to fulfill their potential as therapeutics.
Not surprisingly, Ab engineering has constituted its own field. Mutations can be introduced in the variable regions to increase the affinity of the Ab for its antigen or in the constant region to enhance its natural effector functions. Pharmacokinetics and avidity are improved by multimerization of Ab fragments. Ab molecules have been dissected to their basic elements, and then rearranged to produce a variety of formats not found in nature that display new properties. Moreover, these "building blocks" have been incorporated into multiple types of fusion proteins, soluble (immunocytokines, immunotoxins), as well as part of artificial cell surface receptors and viral envelopes for the retargeting of both effector cells and virus particles (Figure 1).
Making better mAb: how to improve their "natural" effector functions
Ab contains two functionally and molecularly separable
modules (Figure 1A): one module for antigen binding (Fab)
and another for triggering effector functions (Fc). The
antigen-binding region can be manipulated to increase both
binding affinity and specificity. Methods of Ab affinity
maturation are based on the principle of changing parts of the
variable domains while keeping the specificity. Different
approaches are: chain-shuffling (substitution of the native light
chain with a new light-chain repertoire, but retaining the
variable heavy chain), randomization of complementarity
determining regions (CDR), and generation of Ab libraries with
mutations within the variable regions by error-prone PCR,
and E coli mutator strains or site-specific
mutagenesis[4].
Fragment cystalizable (FC) domains contain motifs for
the activation of both effector immune cells and the classical
pathway of the complement (C1q) responsible, respectively,
for Ab-dependent cellular cytotoxicity (ADCC) and
complement-dependent cytotoxicity (CDC). A variety of immune
cells express on their surface receptors for the Fc domain of
IgG1 and IgG3: FcgRI, FcgRIIa, FcgRIII are stimulatory and
FcgRIIb is inhibitory. The Fc domain sequence can be
manipulated (Figure 1A) to increase its affinity for the
stimulatory receptors or to decrease its binding to the inhibitory
one, modulating the activity of the whole
Ab[5]. Similarly, point mutations in the Fc domain can increase the binding to
C1q, improving complement activation[6]. Modification of
Fc glycosylation can also enhance its ability to support
ADCC[7].
The Fc region of human Ab also contains a binding motif
for the receptor FcRn that protects immunoglobulins (Ig) from
intracellular degradation (Figure 1A). By contrast, rodent mAb
fail to bind to FcRn and are rapidly removed from the circulation.
Using combinatorial phage display libraries, mutations in the
Fc region have been identified with higher binding affinity to
FcRn, implying longer half-life of the
mAb[8].
New formats, new functions
The domain architecture of Ig has facilitated the creation
of both smaller and larger forms with variable valency for
one or more target antigens and pharmacokinetic properties
that are tunable to specific
settings[9]. Non-natural Ab formats (Figure 1C), such as the single-chain fragment variable
(scFv) and the diabody, are rapidly emerging as key players
in the engineered Ab field. A scFv (??30 kDa) comprises the
V domains of the heavy and light chains (VH and VL) of a
mAb joined by a linker sequence[3]. A diabody (??60) kDa is
produced when scFv contain short interdomain linkers (5
aminoacids or less)[10]. This prevents intramolecular pairing
of the VH and VL domains on the same chain, but allows
interchain pairing to form dimers. Reducing further the linker
length promotes the assembly of scFv into trimers
(tria-bodies, ??90 kDa) or tetramers (tetrabodies, ??120
kDa). The increased binding valency of these multimers results in high
avidity and low off-rates.
Given that Ab fragments lack the Fc region, their
biological effects can not be attributed to CDC or ADCC. In this
context, the nature of the target is crucial, as Ab fragments
function by blocking the action of specific molecules or by
acting as signaling molecules. The blocking activity is
achieved by preventing growth factors, cytokines or other
soluble mediators reaching their target receptors,
accomplished either by the Ab binding to the factor itself or to its
receptor. The signaling effect is based on the crosslinking
of receptors that are, in turn, connected to mediators of cell
division or programmed cell death[4].
Diabodies constitute the most effective way to generate
bispecific Ab fragments through their ability to bind to 2
different antigens and used to crosslink various cells and
molecules. Bispecific Ab offer a variety of new effector
mechanisms: retargeting of effector cells (cytotoxic T cells,
NK cells, and macrophages), recruitment of effector
molecules (toxins, drugs, prodrugs, cytokines, radioisotopes,
and complement system) and retargeting of carrier systems
(viral vectors for gene therapy)[11].
Ab fragments as Fab and scFv offer several advantages
because of their small size when compared to parental Ig
(150 kDa): (i) they are easy to produce in bacterial systems;
(ii) extravasate more efficiently; and (iii) their tissue
penetration ability is higher. However, recombinant proteins that
are smaller than 60 kDa are taken up by the kidney and
excreted into the urine. Therefore, these molecules tend to
have a short circulating half-life. As Fab and scFv fragments
lack the Fc region altogether, they can not be saved from
degradation by FcRn. Multimerization is an obvious
strategy to increase the size, and therefore, the half-life of Ab
fragments (triabodies, tetrabodies). The use of bispecific
Ab fragments for retargeting serum Ig provides with the
Fc-associated effector functions and prolongs the residence
time in serum. A new approach is the pegylation of Ab
fragments, achieved by chemical coupling of polyethylene
glycol (PEG) to amino groups in the protein structure,
increasing the size of the molecule above the glomerular
filtration limit[12].
Naked versus armed mAb: acquisition of new effector functions
In cancer therapy, Ab fragments are fused (chemically or
at genetic level) with a range of molecules to introduce
different functionalities, including cytotoxic drugs, toxins, or
radionuclides for cancer cell killing, enzymes for prodrug
therapy and cytokines to stimulate the antitumor immune
response (Figure 1D). These "armed" Ab exhibit
considerably better therapeutic performance than their "naked"
counterparts (for a review on the topic, see Ref [2]).
Incorporation of agents with direct toxic
effect The most widely explored strategy for enhancing the efficacy of
antitumor Ab is direct arming by linkage to cytotoxic agents or
radionuclides. In fact, 3 of the approved mAb for use in
patients belong to this group: gemtuzumab ozogamicin was
the first (2000), followed by ibritumomab tiuxetan and
tositumomab (2002 and 2003, respectively). Gemtuzumab
ozogamicin is an anti-CD33 (antigen expressed in 90% of
acute myeloid leukemias) mAb conjugated to calicheamicin.
Calicheamicins and maytansinoids are (100-1000)-fold more
potent than conventional chemotherapeutics and constitute
the most extensively evaluated small-molecule toxins used for
Ab arming[2]. Biological toxins, such as ricin or diphtheria
toxin, can be attached to an Ab (native Ig or recombinant
fragments), although their clinical application has been
hampered by their high toxicity. It has recently been published
that a single point mutation in ricin toxin can eliminate
vascular damage without compromising its
action[13].
Ibritumomab tiuxetan and tositumomab are anti-CD20
mAb conjugated, respectively, to 90Y and
131I, and approved for non-Hodgkin lymphoma treatment. Radioimmunotherapy
(RAIT/RIT) has the advantage to kill bystander cells,
especially interesting when not all the tumor cells express the
antigen recognized by the Ab[14].
ADEPT: Ab-directed enzyme prodrug
therapy ADEPT involves the pre-targeting of prodrugs to tumors. An
Ab-enzyme fusion protein is first administered and allowed to
localize to the tumor, followed by the administration of the
prodrug which is activated by the enzyme at the tumor
site[15,16]. This strategy has proven highly effective in
preclinical tumor models, allowing 4-12 fold higher intratumor
drug concentrations and up to 5-fold lower extratumor drug
concentration[2]. An interesting approach is the use of Abs
with inherent catalytic activity, so the conjugation to an
enzyme is not required[17].
Immunocytokines Several cytokines have demonstrated
their potent antitumoral effect, but unfortunately their side
effects limit their administration. In order to accumulate
preferentially the cytokine in the tumor, fusion proteins
(immunocytokines) consisting of a targeting mAb specific
for a tumor antigen and the selected cytokine (IL-2, IL-12,
TNF-a and GM-CSF) have been
designed[18]. These immunocytokines allow the local activation of the
antitumoral immune response, avoiding the toxicity associated with
systemic cytokine administration[19,20]. A different approach
is based on the targeting of tumor vasculature using
cyto-kines with recognized antiangiogenic effect, as
IL-12[21].
Gene therapy: new scenarios
The practical utility of Ab fragments has been limited by
problems related to large-scale production and
biodistri-bution. Monovalent Ab fragments exhibit rapid blood
clearance and poor retention time on the target, which results in
the necessity of frequent delivery of such Ab fragments. To
circumvent these limitations, Ab-based gene therapy
approaches have been developed. In vivo production makes
the Abs less immunogenic and better tolerated and results in
effective and persistent levels of Ab fragments,
compensating for the rapid blood clearance of scFvs. Moreover,
genetic approaches provide Ab molecules with new functions
in unexpected scenarios[22].
Secretion of soluble Abs by genetically modified
cells In vivo production of therapeutic mAb by genetically
engineered cells could advantageously replace the injection of
purified Ab in cancer treatment. The feasibility of the
in vivo production and systemic delivery of mAb by different
cells/tissues has now been demonstrated using different
techni-ques, as ex vivo genetically modified autologous or
encapsulated heterologous cells and in vivo gene transfer using
viral vectors[23].
In the first work reporting a therapeutic effect associated
to in vivo mAb production, an anti-erbB-2 scFv was
expressed using an adenoviral vector. In this model, a human
ovarian cancer cell line erbB-2+ was established in the
context of athymic nude mice. Whereas exponential growth in
tumor volumes was noted in the control groups, a clear
inhibition of tumor growth was observable for the animals treated
with the adenoviral vector encoding anti-erbB-2
scFv[24].
We have demonstrated that both monospecific and
bispecific Ab can be efficiently produced by mammalian cells
with a clear therapeutic effect. Using an anti-laminin scFv
with antiangiogenic activity[25,26], we assessed that
gene-modified human fibrosarcoma cells failed to grow to
detectable tumors when inoculated in athymic
mice[27]. In another set of experiments, functionally active diabody (anti-CEA x
anti-CD3) was secreted from stably transfected human cells
and promoted unstimulated human primary T cells to
proliferate and kill CEA-expressing cancer cells. Importantly,locally produced diabodies showed significant cytotoxic
activity in vivo against established tumors and only required
the infusion of small numbers of functional T
cells[28].
Surface-bound Abs: chimeric immune
receptors Adoptive cellular immunotherapy of cancer has been limited mostly
because of the poor immunogenicity of tumor cells and the
difficulties in obtaining tumor-specific MHC-restricted
cytotoxic T lymphocytes (CTL) in large
numbers[29]. To circumvent these limitations, new strategies have been designed
in order to target CTL to relevant tumor cell surface antigens,
including genetic manipulation of T cells to graft them with
new recognition specificities[30].
Chimeric immune receptors (CIR) genes are composed of
a recognition unit attached to the transmembrane and
intracytoplasmic sequences of a signaling molecule. Most
Ab-derived CIR use scFvs as recognition domains. Signaling
molecules belong to a family of structurally and functionally
related proteins that include TCR-associated polypeptides
and some Fc receptors. As the requirements of MHC
restriction are bypassed, the tumor cell recognition of CTL grafted
with CIR is not hampered by the down-regulation of HLA
class I molecules usually found in
tumors[30].
The utility and effectiveness of the CIR approach has
been demonstrated in a variety of animal models where
tumor-specific CIR drove the adoptive transferred autologous
T-lymphocytes to accumulate at the tumor site in
vivo and prevented the growth of syngenic tumors that grow rapidly
in the native host. Target antigens include CEA (colorectal
cancer), PSMA (prostate cancer), erbB-2 (breast and others),
CD19 and CD20 (B-cell malignancies), CD30 (lymphomas),
GD2 (neuroblastoma) and the tumor neovasculature
receptor VEGFR-2[22]. Recently, human peripheral blood
leukocytes genetically modified to target CD19 were shown to
eliminate systemic B-cell tumors in immunodeficient
mice[31]. Primarily investigated in T cells, CIR have also proven
useful in the retargeting of NK
cells[32].
Recent studies have established that the provision of
additional or co-stimulatory signals is essential for the
expansion and activity of adoptively transferred T cells.
We have reported that CD28-based CIRs were stably expressed
as functional cell surface receptors and that Ag-specific
co-stimulatory signals could synergize with signals mediated
through the native TCR/CD3 complex or TCRz-based CIR to
produce optimal levels of IL-2[33]. Moreover, CIR providing
both primary and costimulatory signaling in T cells from a
single gene product have been
described[34].
Viral surface engineering Most of the viral vectors
developed for gene therapy have a broad tissue tropism.
The development of viral vectors targeted into a selected
type of cell or tissue, without losing virus infection efficiency
or causing toxicity, is critical for their clinic application.
Cancer cells represent major targets in this strategy, as they
often express lower levels of viral receptors compared to
normal cells[35].
Using Ab directed against tumor-associated antigens
expressed on the cell surface for virus pseudotyping has
been successfully associated with different viral vectors in
directing them to cancer cells. Adenovirus (AdV) has been
extensively studied in this approach, especially in the
context of capsid engineering. The most recent developments
in this approach have overcome several limitations in this
strategy, including the need for correct ligand folding, the
structural and biosynthetic compatibility of ligands with the
AdV, along with the fact that in this strategy, viruses have
to be specifically engineered for each particular targeting
situation. Thus, several groups have used similar strategies
by incorporating an IgG-binding domain of staphylococcal
protein A into the AdV fiber protein, allowing the vectors to
form a stable complex with either full size mAb or fusion
proteins consisting of a targeting scFv fused to an Ig Fc
domain[36,37].
Another group of preferred vectors in preclinical and
clinical settings for cancer gene therapy are the murine leukemia
virus (MLV)-based retroviral vectors. Several groups have
inserted a scFv moiety in the virus envelop to obtain
cell-specificity[38-41]. Using a different strategy, the IgG-binding
domain of protein A was inserted into the envelope, allowing
the redirecting lentiviral vectors to target cells through
adaptors as described for AdV[42].
The attenuated measles virus (MV) is another vector with
great therapeutic potential in gene therapy. The feasibility
to expand MV tropism by virtue of a scFv displayed on its H
protein was demonstrated using an anti-CEA
scFv[43]. Replicating MV have been obtained which are capable of
entering CD20+ or CD38+ target cells through interaction between
either an anti-CD20 or anti-CD38 scFv and the cognate
antigen molecules on the cell surface. Both studies have shown
significant antitumor effects in
vivo[44,45].
Intrabodies Intracellular Ab (intrabodies) constitute
neutralizing molecules with a great potential in gene therapy and
represent an alternative to other methods of gene
inactivation as antisense RNA and RNA interference (RNAi). When
provided with the corresponding protein trafficking signals,
intrabodies can be directed to endoplasmic reticulum via
addition of a SEKDEL retention signal, nucleus via the
SV40-derived nuclear localization signal, inner face of the plasma
membrane by the addition of farnesylation signals or
cytoplasm simply by the deletion of the leader peptide. Although
classically designed to divert proteins from their usual
cellular compartment or to block protein-protein or protein-nucleic
acid interactions, this concept is currently in expansion, with
intrabodies capable of directly inhibiting the function of an
enzyme, activating intracellular proteins, as caspase-3, or
leading proteins to degradation in the ubiquitin-proteasome
pathway using F-box-intrabody
fusions[46].
ScFvs are the preferred format for intrabodies, but their
stability is affected by the reducing conditions inside the
cell, which prevent the formation of intradomain disulphide
bonds and blocks their proper folding. Efforts to generate
functional intrabodies include the isolation of naturally
occurring intrabodies from large libraries and the creation of an
artificial intrabody framework that relies on the
pre-determined ability of certain scFv to fold adequately and remain
stable in the cellular milieu[46,47]. While scFv intrabodies are
the most common, alternative formats have been shown to
be equally effective, including single Ab domains
("came-lized" or not) and bispecific Ab, known as "intra-diabodies"
which are able to downregulate simultaneously 2 cell surface
receptors[48].
Regarding their application in cancer therapy, intrabodies
are suitable to downregulate proteins overexpressed in
tumors, such as EGFR, erbB-2, cathepsin
L[49], and cyclin E or to target mutant oncogenic forms of Ras and p53 and
fusion proteins as BCR-ABL. Apoptosis of tumor cells can
be promoted by downregulation of Bcl-2 or activation of
caspase-3, and the uptake of cytotoxic drugs can be increased
blocking the multidrug resistance (MDR) gene
product[22]. Inhibition of tumor neovascularization is a promising
approach for cancer therapy. Recently, an adenoviral vector
was used to deliver a scFv capable of blocking surface
expres-sion of an endothelial cell-specific receptor and significantly
inhibited growth of human xenografts in a murine
model[50].
Conclusions
Antibody engineering represents an emerging
technology that holds great promise for medical science. With the
plethora of new molecular techniques at hand, many
innovative approaches to diagnostics and therapeutics applications
are under consideration. The development of protein
engineering techniques to reduce immunogenicity, alter half-life,
improve efficacy, and increase tumor targeting has
provided the new types of antibodies that are moving rapidly from the
bench to the clinic. In fact, engineered antibodies now
represent over 30% of biopharmaceuticals in clinical trials.
Furthermore, genetic approaches provide antibody molecules
with new functions in unexpected scenarios: expression of
antibody domains in precise intracellular locations and
grafting of new binding activities to engineered cells. Further
improvement will require the design of in
vivo selection systems to generate antibodies fully active in specific cellular
compartments, and the use of antibodies as tools for
functional gene identification and drug target validation
(genomics- and proteomics-based high-throughput systems)
and for better understanding of disease pathways.
References
1 Kohler G, Milstein C. Continuous cultures of fused cells secreting
antibody of predefined specificity. Nature 1975; 256: 495-7.
2 Carter P. Improving the efficacy of antibody-based cancer
therapies. Nat Rev Cancer 2001; 1: 118-29.
3 Hudson PJ, Souriau C. Engineered antibodies. Nat Med 2003; 9:
129-34.
4 Brekke OH, Sandlie I. Therapeutic antibodies for human diseases
at the dawn of the twenty-first century. Nat Rev Drug Disc 2003;
2: 52-62.
5 Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J,
et al. High resolution mapping of the binding site on human IgG1
for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and
design of IgG1 variants with improved binding to the Fc gamma
R. J Biol Chem 2001; 276: 6591-604.
6 Idusogie EE, Wong PY, Presta LG, Gazzano-Santoro H, Totpal
K, Ultsch M, et al. Engineered antibodies with increased activity
to recruit complement. J Immunol 2001; 166: 2571-5.
7 Umaña P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE.
Engineered glycoforms of an antineuro-blastoma IgG 1 with
optimized antibody-dependent cellular cytotoxic activity. Nat
Biotechnol 1999; 17: 176-80.
8 Ghetie V, Popov S, Borvak J, Radu C, Matesoi D, Medesan C,
et al. Increasing the serum persistence of an IgG fragment by
random mutagenesis. Nat Biotechnol 1997; 15: 637-40.
9 Pluckthun A. Mono- and bivalent antibody fragments produced
in Escherichia coli: engineering, folding and antigen binding.
Immunol Rev 1992; 130: 151-88.
10 Holliger P, Prospero T, Winter G. "Diabodies": small bivalent
and bispecific antibody fragments. Proc Natl Acad Sci USA 1993;
90: 6444-8.
11 Kontermann RE. Recombinant bispecific antibodies for cancer
therapy. Acta Pharmacol Sin 2005; 26: 1-9.
12 Natarajan A, Xiong CY, Albrecht H, DeNardo GL, DeNardo
SJ. Characterization of site-specific ScFv PEGylation for
tumor-targeting pharmaceuticals. Bioconjug Chem 2005; 16:113-21.
13 Smallshaw JE, Ghetie V, Rizo J, Fulmer JR, Trahan LL, Ghetie
MA, et al. Genetic engineering of an immunotoxin to eliminate
pulmonary vascular leak in mice. Nat Biotechnol 2003; 21:
387-91.
14 Goldenberg DM. Advancing role of radiolabeled antibodies in the
therapy of cancer. Cancer Immunol Immunother 2003; 52:
281-96.
15 Xu G, McLeod HL. Strategies for enzyme/prodrug cancer therapy.
Clin Cancer Res 2001; 7: 3314-24.
16 Sharma SK, Pedley RB, Bhatia J, Boxer GM, El-Emir E, Qureshi
U, et al. Sustained tumor regression of human colorectal cancer
xenografts using a multifunctional mannosylated fusion protein
in antibody-directed enzyme prodrug therapy. Clin Cancer Res
2005; 11: 814-25.
17 Shabat D, Lode HN, Pertl U, Reisfeld RA, Rader C, Lerner RA,
et al. In vivo activity in a catalytic antibody-prodrug system:
antibody catalyzed etoposide prodrug activation for selective
chemotherapy. Proc Natl Acad Sci USA 2001; 98: 7528-33.
18 Nissim A, Gofur Y, Vessillier S, Adams G, Chernajovsky Y.
Methods for targeting biologicals to specific disease sites. Trends Mol
Med 2004; 10: 269-74.
19 Hombach A, Heuser C, Abken H. Simultaneous targeting of IL2
and IL12 to Hodgkin's lymphoma cells enhances activation of
resting NK cells and tumor cell lysis. Int J Cancer. 2005; 115:
241-7.
20 Gillies SD, Lan Y, Williams S, Carr F, Forman S, Raubitschek
A, et al. An anti-CD20-IL-2 immunocytokine is highly efficacious
in a SCID mouse model of established human B lymphoma. Blood.
2005; 105: 3972-8.
21 Halin C, Rondini S, Nilsson F, Berndt A, Kosmehl H, Zardi L,
et al. Enhancement of the antitumor activity of interleukin-12 by
targeted delivery to neovasculature. Nat Biotechnol 2002; 20:
264-9.
22 Sanz L, Blanco B, Alvarez-Vallina L. Antibodies and gene therapy:
teaching old `magic bullets' new tricks. Trends Immunol 2004;
25: 85-91.
23 Pelegrin M, Gros L, Dreja H, Piechaczyk M. Monoclonal
antibody-based genetic immunotherapy. Curr Gene Ther 2004; 4:
347-56.
24 Arafat WO, Gomez-Navarro J, Buchsbau DJ, Xiang J, Wang M,
Casado, et al. Effective single chain antibody (scFv)
concentrations in vivo via adenoviral vector mediated expression of
secretory scFv. Gene Ther 2002; 9: 256-62.
25 Sanz L, Kristensen P, Russell SJ, Ramirez Garcia JR,
Alvarez-Vallina L. Generation and characterization of recombinant
human antibodies specific for native laminin epitopes: potential
application in cancer therapy. Cancer Immunol Immunother
2001; 50: 557-65.
26 Sanz L, Garcia-Bermejo L, Blanco FJ, Kristensen P, Feijoo M,
Suarez E, et al. A novel cell binding site in the coiled-coil domain
of laminin involved in capillary morphogenesis. EMBO J 2003;
22: 1508-17.
27 Sanz L, Kristensen P, Blanco B, Facteau S, Russell SJ, Winter
G, et al. Single-chain antibody-based gene therapy: inhibition of
tumor growth by in situ production of phage-derived human
antibody fragments blocking functionally active sites of
cell-associated matrices. Gene Ther 2002; 9: 1049-53.
28 Blanco B, Holliger P, Vile R, Alvarez-Vallina L. Induction of
human T lymphocyte cytotoxicity and inhibition of tumor
growth by tumor-specific diabody-based molecules secreted from
gene-modified bystander cells. J Immunol 2003; 171: 1070-7.
29 Baxenavis CN, Papamichail M. Targeting of tumor cells by
lymphocytes engineered to express chimeric receptor genes. Cancer
Immunol Immunother 2004; 53: 893-903.
30 Álvarez-Vallina L. Genetic approaches for antigen-selective cell
therapy. Curr Gene Ther 2001; 4: 385-97.
31 Brentjens RJ, Latouche JB, Santos E, Marti F, Gong MC, Lyddane
C et al. Eradication of systemic B-cell tumors by genetically
targeted human T lymphocytes co-stimulated by CD80 and
interleukin-15. Nat Med 2003; 9: 279-86.
32 Uherek C, Tonn T, Uherek B, Becker S, Schnierle B, Klingemann
HG, et al. Retargeting of natural killer-cell cytolytic activity to
ErbB2-expressing cancer cells results in efficient and selective
tumor cell destruction. Blood 2002; 100: 1265-73.
33 Alvarez-Vallina L, Hawkins RE. Antigen-specific targeting of
CD28-mediated T cell co-stimulation using chimeric single-chain
antibody variable fragment-CD28 receptors. Eur J Immunol 1996;
26: 2304-9.
34 Finney HM, Lawson AD, Bebbington CR, Weir AN. Chimeric
receptors providing both primary and costimulatory signaling in
T cells from a single gene product. J Immunol 1998; 161:
2791-7.
35 Sanz L, Qiao J, Vile R, Alvarez-Vallina L. Antibody engineering,
virus retargeting and cellular immunotherapy: one ring to rule
them all? Curr Gene Ther 2005; 5: 63-70.
36 Korokhov N, Mikheeva G, Krendelshchikov A, Belousova N,
Simonenko V, Krendelshchikov V, et al. Targeting of adenovirus
via genetic modification of the viral capsid combined with a
protein bridge. J Virol 2003; 77: 12931-40.
37 Volpers C, Thirion C, Biermann V, Hussmann S, Kewes H, Dunant
P, et al. Antibody-mediated targeting of an adenovirus vector
modified to contain a synthetic immunoglobulin g-binding
domain in the capsid. J Virol 2003; 77: 2093-104.
38 Russell SJ, Hawkins RE, Winter G. Retroviral vectors displaying
functional antibody fragments. Nucleic Acids Res 1993; 21:
1081-5.
39 Somia NV, Zoppe M, Verma IM. Generation of targeted retroviral
vectors by using single-chain variable fragment: an approach to
in vivo gene delivery. Proc Natl Acad Sci USA 1995; 92: 7570-4.
40 Chu TH, Dornburg R. Toward highly efficient cell-type-specific
gene transfer with retroviral vectors displaying single-chain
antibodies. J Virol 1997; 71: 720-5.
41 Martin F, Neil S, Kupsch J, Maurice M, Cosset F, Collins M.
Retrovirus targeting by tropism restriction to melanoma cells. J
Virol 1999; 73: 6923-9.
42 Morizono K, Xie Y, Ringpis GE, Johnson M, Nassanian H, Lee
B, et al. Lentiviral vector retargeting to P-glycoprotein on
metastatic melanoma through intravenous injection. Nat Med 2005;
11: 346-52.
43 Hammond AL, Plemper RK, Zhang J, Schneider U, Russell SJ,
Cattaneo R. Single-chain antibody displayed on a recombinant
measles virus confers entry through the tumor-associated
carcinoembryonic antigen. J Virol 2001; 75: 2087-96.
44 Bucheit AD, Kumar S, Grote DM, Lin Y, von Messling V, Cattaneo
RB, et al. An oncolytic measles virus engineered to enter cells
through the CD20 antigen. Mol Ther 2003; 7: 62-72.
45 Peng KW, Donovan KA, Schneider U, Cattaneo R, Lust JA,
Russell SJ. Oncolytic measles viruses displaying a single-chain
antibody against CD38, a myeloma cell marker. Blood 2003;
101: 2557-62.
46 Lobato MN, Rabbits TH. Intracellular antibodies and challenges
facing their use as therapeutic agents. Trends Mol Med 2003; 9:
390-6.
47 Stocks MR. Intrabodies: production and promise. Drug Discov
Today 2004; 9: 960-6.
48 Jendreyko N, Popkov M, Beerli RR, Chung J, McGavern DB,
Rader C et al. Intra-diabodies: bispecific, tetravalent antibodies
for the simultaneous functional knockout of two cell surface
receptors. J Biol Chem 2003; 278: 47812-9.
49 Rousselet N, Mills L, Jean D, Tellez C, Bar-Eli M, Frade R.
Inhibition of tumorigenicity and metastasis of human melanoma cells
by anti-cathepsin L single chain variable fragment. Cancer Res
2004; 64: 146-51.
50 Popkov M, Jendreyko N, McGavern DB, Rader C, Barbas CF III.
Targeting tumor angiogenesis with adenovirus-delivered
anti-Tie-2 intrabody. Cancer Res 2005; 65: 972-81.
|
