Download Monoclonal antibodies as enhancers of the host`s immunoresponse

Monoclonal antibodies as enhancers of the host's immunoresponse
against the tumour
Hakan Mellstedt
Cancer Center Karolinska, Department of Oncology, Karolinska Hospital, Stockholm, Sweden
Introduction
antigen with a certain degree of specificity even if
the normal counterpart is a cell structure of a normal
non-transformed cell.
Monoclonal antibodies (MAb) might induce tumour
cell death by a multitude of mechanisms of actions.
Principally monoclonal antibodies can be used unconjugated or conjugated to a toxic substance. So
far, unconjugated MAb have been most successful
and used extensively for treatment of malignant diseases. Several unconjugated therapeutic monoclonal
antibodies are on the market and there are a lot more
to be launched.
Unconjugated MAb have two fundamentally different ways of action. If the MAb recognise a target
structure involved in cell proliferation or apoptosis,
the MAb may cause programmed cell death or tumour cell cycle arrest by binding to the relevant
domain of the tumour antigen and deliver a signal
inducing tumour destruction in vivo without activating the immune system [1]. Monoclonal antibodies
may also enhance various immune effector functions which can mediate tumour cell destruction.
Immune functions which spontaneously might kill
tumour cells include antibodies, unspecific cytotoxic
cells (monocytes/macrophages, NK cells, granulocytes, eosinophils) and specific killer cells (various T
lymphocyte subsets). In this paper, host's immune responses against the tumour enhanced by monoclonal
antibodies are reviewed.
Monoclonal antibodies interactions with the
immune system
MAb might induce tumour cell death by activating
various immune effector functions (Table 1).
Monospecific antibodies and ADCC
Cells participating in ADCC (monocytes/macrophages, NK cells, granulocytes) express IgG Fcreceptors. The human Fc-part of the immunoglobulin molecule more efficiently interacts with human
Fc-receptors than the mouse IgG Fc-region. Thus,
chimeric, humanised ('CDR'-grafted) and human
MAb are more effective in activating ADCC activities than mouse MAb and should therefore in this regard be of preference to utilise. To increase the ADCC
capability, cytokines might be added which enhance
various immune effector functions, not only ADCC,
utilised by monoclonal antibodies (Table 2).
These cytokines might also augment the intratumoural unspecific inflammatory response, and thereby
contribute to an increased bystander killing [3].
Recognition structure
A lot of antigenic structures in various malignancies
are available for passive specific immunotherapy. It is
generally considered that structures which can evoke
a natural humoral IgG response should preferentially
be utilised for antibody therapy. Using the SEREX
technology more than 600 different tumour antigens
have been identified able to induce a spontaneous
anti-tumour IgG response [2]. Such a host response
indicates that the antigen is altered from self and an
Table 1
Immune mediated mechanisms of actions of monoclonal antibodies
ADCC (antibody dependent cellular cytotoxicity)
CDC (complement dependent cytolysis)
Induction of inflammatory response/bystander killing
Induction of an idiotypic network response/humoral and cellular
anti-tumour immunity
191
192
H. Mellstedt
Table 2
Cytokines to combine with therapeutic MAb to enhance the host's immune responses
Cytokine
Activating immune functions
GM-CSF
M-CSF
G-CSF
IL-2
ot/y-Interferon
ADCC
ADCC
ADCC
ADCC
ADCC
(monocytes/macrophages, granulocytes, NK cells), idiotypic network response (antigen presentation)
(monocytes/macrophages)
(granulocytes)
(monocytes/macrophages, NK cells), expand tumour specific T cells
(monocytes/macrophages, NK cells) upregulate tumour antigens, expand tumour specific T cells
Bispecific monoclonal antibodies
An increased recruitment of effector cells to the
tumour lesion might also be achieved by using bispecific antibodies binding with one F(abi)-arm to the
tumour cells and the other to effector cells. Examples
of recognition structures on effector cells utilised
for bispecific monoclonal antibody constructs are
CD 16 (NK cells, monocytes), CD64 (monocytes,
activated granulocytes), CD3 (T cells), CD28 (signalling molecule on T cells) etc. The monovalent
binding to the effector cells must induce a signal
activating the immune cells with release of lytic
proteins, otherwise antibody treatment has to be
combined with cytokines activating the appropriate
effector cell. Bispecific antibodies binding to various
effector surface cell structures are in clinical testing.
The idiotypic network cascade
According to the idiotypic network theory by N.
Jerne antibodies and cells interact through idiotypes
to maintain immune homeostases [4]. This hypothesis is applicable for the therapeutic effect of MAb.
When a therapeutic antibody (idiotypic antibody,
abi) is given an immune response is induced against
the idiotypes of abi (CDR (complementary determining region)). Antibodies recognising idiotypes of abi
are called anti-idiotypic antibodies (ab2). A complementary T cell response is also induced (T 2 ). Amino
acid sequences within the CDR regions of ab^ have
homologies with sequences of the nominal antigen
recognised by abi. Thus, at>2 represent an 'internal
image of the antigens'. According to the theory,
an immune response is induced against idiotypic
structures of ab2- Antibodies against CDR regions
of ab 2 are called anti-anti-idiotypic antibodies (ab3)
which have the same specificity as abi and can thus
bind to the tumour antigen and induce tumour lysis
by ADCC and CDC. Also a T cell response (T3)
is evoked which recognise peptides of the nominal tumour antigen presented by MHC molecules
on the tumour cells. The mechanism for induction
of a T3 response is not quite clear. Other mechanisms than presentation of ab2 idiotypic peptides
Therapeutic MAb
Idiotypic MAb
AnU-anti-Wiotypic
antibody Ab,
Antigen-presenting cells
present Ab, to the
Immune system
Anti-ioTolypic antibody
Ab,
Antigen-presenting eel
Internal image ol the antigen'
Fig. 1. Presentation of an idiotypic network response in MAb (abi) treated patients. T2 = cells recognising idiotypic/isotypic structures
on abi. T3 = T cells recognising idiotypic structures on at>2 and the nominal antigen. Thi = CD4 T helperi cells with delayed type
histosensitivity reactivity.
Monoclonal antibodies as enhancers of the host's immunoresponse against the tumour
by antigen presenting cells are probably operating.
A schematic presentation of the idiotypic network
applicable for therapeutic monoclonal antibodies is
depicted in Fig. 1.
Several studies have shown the induction of an at>3
response in patients given monoclonal antibodies.
Induction of an ab3 response has been shown to statistically significant correlate to the clinical outcome
[5,6]. Moreover, in a few studies a tumour directed
T3 response has also been shown and indicated to be
of clinical importance [7,8]. Phenotypically, T3 cells
seemed to be of type I of the CD4 phenotype.
Comparison of the ability of mouse MAb as
opposed to chimeric or humanised monoclonal antibodies to induce an idiotypic response is scanty.
Mouse MAb 17-1A was superior compared to the
chimeric variant in inducing an ab2 response [6].
Further studies are required to fully elucidate this
issue but it might be expected that mouse MAb may
be more efficient in inducing an idiotypic network
response than the chimeric or humanised variants as
the 'foreign' Fc-part of the mouse monoclonal antibodies may be a stronger adjuvant than the human
Fc-part.
The idiotypic network response can be augmented
by adding cytokines. GM-CSF activates dendritic
cells and has been shown to increase the frequency
of patients mounting an ab3 response as well as the
ab3 titres [6]. EL-2 might also be of value as it might
expand tumour antigen specific T3 cells.
Furthermore, the induction of an idiotypic network response is probably most efficient when the
tumour load is low, and when the production of
tumour derived suppressive factors is minimal. This
particular mechanism of action favours the use of
monoclonal antibodies in the adjuvant setting.
Monoclonal antibodies activating specific T cell
responses
193
plastic B cells through a signalling event and thereby
increase the load of tumour antigens to be presented
by anti-CD40 monoclonal antibodies activated APC
[9]. Such antibodies are now going into clinical testing and might also be used in non-haematological
malignancies as well for activation of APC to increase the capacity of these cells to present tumour
antigens from sequestering tumour cells. Anti-CD40
antibody induced T cell response is mainly of the
CD8 phenotype and does not seem to require the
induction of CD4 helper T cells.
BAT monoclonal antibody
A similar principle as for the anti-CD40 monoclonal antibodies has been reported for an antibody
called BAT [10,11]. In preclinical models this antibody induced tumour regression and prolonged
survival in xenograft models of human tumours.
The antibody seemed to be optimally functioning
if the tumour has induced a tumour specific immune response. The BAT antibody then stimulates
proliferation/activation of T cells and NK cells to
reject the tumour. The recognition structure for this
antibody is not yet defined, but the antigen is present
on B cells, T cells and NK cells.
Anti-CD40 and BAT MAb are examples of two
antibodies which utilise a quite new target for monoclonal antibody therapy of cancer, i.e. anti-tumour
immune effector cells and not the tumour cells themselves. This therapeutic principle seems to require
the presence of anti-tumour lymphocytes. The existence of natural occurring tumour specific T cell
immunity seems to be frequently encountered than
expected for many tumours. Moreover, the immune
system is most likely best preserved in the adjuvant
setting which supports the notion that also these antibodies should preferentially be given to patients in
the adjuvant setting, i.e. after removal of the massive
tumour load, which previously has induced a tumour
specific cellular immune response.
Anti-CD40 monoclonal antibodies
CD40 is an essential structure for activation of antigen presenting cells (APC) and B cells. In experimental systems, anti-CD40 monoclonal antibodies
have been shown to eradicate large lymphomas. The
mechanism of action is most likely explained by
activation of a specific T cell response against the
tumour. Binding of CD40 MAb to neoplastic B cells
may render these cells more immunogenic. The antibody might also activate APC which presents tumour
antigens from destroyed tumour cells. In addition
anti-CD40 MAb might also induce apoptosis of neo-
Concluding remarks
Unconjugated monoclonal antibodies use multiple
mechanisms to destroy tumour cells in vivo. Antibodies may bind to tumour cells and interact with
the immune system to kill tumour cells preferentially
by activating cytotoxic cells, induce an unspecific
inflammatory response and an anti-tumour immunity
through the idiotypic network. Monoclonal antibodies might also directly bind to anti-tumour immune
effector cells and enhance their ability to destroy
194
H. Mellstedt
Table 3
Suggestions for monoclonal antibodies therapy directed to enhance the host's immune responses against the tumour
-
Treat patients when the tumour load is small, e.g. in the
adjuvant setting
-
Use a monoclonal antibody binding to a tumour structure
recognised by the host's immune system
-
Combine the tumour targeting monoclonal antibody with an
antibody activating immune effector cells capable of
recognising the tumour
-
Add cytokines which upregulate tumour antigens, augment the
functional activity of cytotoxic cells, stimulate dendritic cells
and expand tumour specific T cells
tumour cells. All these functional activities can be
enhanced by the addition of various cytokines. Moreover, the capability of the host's immune system
to destroy tumour cells is more pronounced when
the immune system is well preserved, i.e. in the
adjuvant setting. Based on these data, unconjugated
monoclonal antibodies with different mechanisms of
action should be combined together with appropriate
cytokines in the adjuvant setting to exert a maximum
anti-tumour effect. A summary of suggestions for
future directions on the use of unconjugated monoclonal antibodies to enhance the host's immune
responses against the tumour is given in Table 3.
References
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10 Hardy B, Kovjazin R, Raiter A, et al. A lymphocyte-activating
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Dieter K. Hossfeld
Medical University Clinic
Department of Oncology-Hematology
Hamburg, Germany
Laurence Zitvogel
Institut Gustave Roussy
Villejuif, France
Harry A. Drabkin
University of Colorado, Health Sciences Center
Division of Medical Oncology
Denver, USA
Franco Cavalli and Emanuele Zucca
Oncology Institute of Southern Switzerland
Division of Medical Oncology
Bellinzona, Switzerland
Matti S. Aapro
Institut Multidisciplinaire d'Oncologie
Clinique de Genolier
Genolier, Switzerland
Anna Gregor
Western General Hospital
Department of Clinical Oncology
Lothian University Hospitals
NHS Trust, Edinburgh
Scotland, UK
Gilberto Schwartsmann
Hospital de Clinicas de Porto Alegre
Universidade Federal Do Rs
Servico de Oncdlogia Clinicd
Porto Alegre, Brazil
Giuseppe Giaccone
Free University Hospital
Department of Oncology
Amsterdam, Netherlands
Nicholas Pavlidis
University ofloannina, School of Medicine
Department of Medical Oncology
Ioannina, Greece
Anthony Howell
Christie Hospital, CRC Department of Oncology
Manchester, United Kingdom
Eric P. Krenning
Department of Nuclear Medicine
University Hospital and Erasmus University
Rotterdam, The Netherlands
H.F.P. Hillen
University Hospital Maastricht
Department of Internal Medicine
Maastricht, The Netherlands