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Ertumaxomab: a trifunctional
antibody for breast cancer
†Charité Campus Benjamin Franklin, Department of Hematology and Oncology,
Hindenburgdamm 30/31, D-12200 Berlin, Germany
Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3
with preferential binding to activating Fc γ type I/III-receptors, resulting in
the formation of a tri-cell complex among tumour cell, T cell and accessory
cell. Recently, the antibody demonstrated antitumour efficacy against HER2/neu low-expressing tumours resistant to trastuzumab. Data from a completed Phase I study in metastatic breast cancer patients indicates strong immune responses. Owing to efficient tumour cell destruction by humoral and T-cell-dependent mechanisms, differing from conventional HER2/neu directed treatments, and a potential for long-lasting antitumour immunoreactivity, ertumaxomab is at present investigated within Phase II studies enrolling metastatic breast cancer patients even without HER2/neu gene amplification.
bispecific antibody , breast cancer , CD3 , HER/2 neu , immunotherapy ,
Expert Opin. Investig. Drugs (2008) 17(10):1553-1558
EGF family member HER2/neu is overexpressed in tumour specimens of ∼ 25 – 30% of breast cancer patients  and attributed to more aggressive tumour growth and worse prognosis
. In the absence of a natural ligand, hetero-
dimerisation with other members of the EGF family, particularly EGFR (HER1), results in a potent activation of intracellular signalling pathways promoting cell proliferation and survival. Therefore, HER2/neu and EGFR have been intensively pursued as therapeutic targets. Monoclonal antibody trastuzumab targeting the extracellular domain of HER2/neu as well as lapatinib, a small molecular compound inhibiting intracellular receptor signalling of EGFR and HER2/neu are already in clinical use and have demonstrated clinical efficacy both in metastatic and early breast cancer patients
often not as strong as predicted from preclinical studies and combination with chemotherapy is preferable  . Furthermore, clinical efficacy in HER2/neu directed treatment is limited to patients with gene amplification detected by fluorescence
hybridisation (FISH) and/or overexpression of HER2/neu
receptor corresponding to an immunohistochemistry (IHC) score of 3+ [12-14] . Enhancing immunological effector functions of antibodies reflects one approach to improve the efficacy of antibody-based cancer therapy. Bispecific antibodies (BsAb) with two different antigen-binding sites are powerful tools for immuno-logical treatment of malignant cells. Since the pioneering works of Segal et al.
in the 1980s  , numerous BsAbs with different properties and target antigens have been developed and shown to redirect cellular cytotoxicity by simultaneous binding of tumour cells and immune cells. However, the BsAb described until now normally activate only a single class of effector cells, that is, either T cells,
10.1517/13543780802373246 2008 Informa UK Ltd ISSN 1354-3784
All rights reserved: reproduction in whole or in part not permitted
Macrophages, dendritic cells, natural killer cells
Figure 1 . The postulated tri-cell-complex.
Activation and crosstalk of different types of immune cells accelerated by the
ADCC: Antibody-dependent cell-mediated cytotoxicity; CD: Cluster of differentiation; DC-CK1: Dendritic cell cytokine 1; Fc: Crystallisable fragment; IL: Interleukin;
LFA: Leukocyte function associated antigen; NK: Natural killer cell; TNF- α : Tumour necrosis factor α .
NK (natural killer) cells, Fc γ type I receptor (Fc γ RI) positive
cells, that is, macrophages and dendritic cells leading to the
cells, Fc γ type III receptor (Fc γ RIII) or Fc α type I receptor
uptake, processing and presentation of tumour-associated
(Fc α RI) positive cells following binding to an appropriate
proteins ( Figure 1
)  .
target molecule of the effector cell [16-21] .
Finally, as a consequence, a humoral as well as a T-cell
response against HER2/neu and other tumour-associated
2. Characterisation of ertumaxomab
peptides could be induced potentially leading to a long-lasting antitumour immunity facilitated by the involvement
2.1 Mode of action
Ertumaxomab (Fresenius Biotech/Trion Pharma, Munich, Germany) belongs to a new class of BsAb consisting of the
2.2 Preclinical activity
two potent and evolutionary related effector subclasses,
The ability of ertumaxomab to kill HER2/neu-positive
mouse IgG2a and rat IgG2b, with particularly preferential
tumour cells was demonstrated in various in vitro
binding to activating Fc γ RI/III-receptors [22,23] . Produced by
using tumour cell lines of different tumour types and human
a quadroma cell line prepared by fusion of a specific rat
multicellular tumour spheroids cocultured with peripheral
(anti-CD3) and mouse hybridoma cell line (anti-HER2), its
two antigen-binding sites target HER2/neu on tumour ertumaxomab was shown to completely eliminate autologous cells and the CD3 molecule on T cells. Simultaneously,
tumour cells in leukapheresis products of patients with
-receptor positive accessory cells are recruited through
breast cancer contaminated with tumour cells  . In vitro
the Fc-portion  , resulting in the formation of a tri-cell
efficacy of ertumaxomab was compared with the parental
complex with physiological co-stimulation of the T cell and
monoclonal anti-HER2/neu antibody 2502A and trastuzumab
very efficient tumour cell destruction by various immuno-
using PBMC from healthy donors incubated with HER2/neu
logical mechanisms: i) activation of T cells with release of
expressing SKBR3 tumour cells and increasing antibody
cytokines and lytic enzymes [24,25] ; ii) prevention of T-cell
concentrations. Whereas the monospecific murine monoclonal
anergy by the release of co-stimulatory cytokines and a
antibody 2502A revealed only weak antitumour effects, the
crosstalk between co-stimulatory molecules expressed or humanised antibody trastuzumab was able to inhibit tumour upregulated on T cells and accessory cells
cell growth up to ∼ 45% at concentrations ranging from
2.5 – 125 ng/ml. In contrast, the trifunctional antibody
Expert Opin. Investig. Drugs
Kiewe & Thiel
ertumaxomab revealed statistically significant cytotoxicity transient aggravation of pre-existing ventricular dysfunction. rates of 97 – 99% against tumour cells at concentrations as
Transient lymphopenia was seen in most patients, and
low as 50 ng/ml, supporting the concept of enhanced reversible elevation of liver enzymes in almost 50%. Hepatic cytotoxicity by a concerted action of different immune cell
dysfunction was reported in two patients (CTC grade 3
types  . Recently, Jäger et al.
 provided more data by
showing that in the presence of PBMC ertumaxomab
Three patients responded to treatment (one patient with
destroys HER2/neu high-expressing target cells (SKBR3) mediastinal lymph node metastases achieved a complete equally effective as trastuzumab at an optimal effector response, and two patients – one with lung metastases, and cell/target cell ratio (E:T ratio) of 20:1. In a suboptimal
one with retropectoral lymph node metastases – a partial
E:T ratio, which better reflects the situation at the tumour
site, trastuzumab loses its activity whereas ertumaxomab duration of responses, however, was partly obscured by retains its ability to kill the tumour cells. The activity of
concomitant or subsequent endocrine treatment. Cytokine
ertumaxomab is not inhibited by the presence of trastuzumab
measurements revealed secretion of IL-6, IFN- γ and TNF- α ,
indicating the recognition of different epitopes. Moreover,
indicating a Th1-associated immune response. Humoral or
ertumaxomab was able to destroy HER2/neu low-expressing
T-cell responses, particularly those specific for HER/neu,
target cells derived from different carcinomas (HCT-8, were not assessed. Roughly one-third of patients developed BT-20 and SK-LU-1) irrespective of the E:T ratio whereas
antibodies against mouse or rat protein (HAMA/HARA
trastuzumab failed to exert any cytotoxic effect even at an
(human anti-mouse antibody)/(human anti-rat antibody)).
optimal E:T ratio. Stimulation of a Th1-type cytokine release was shown reflecting the engagement of CD3 positive
3.2 Future development
T cells and Fc γ -receptor positive accessory cells.
At present, three Phase II studies are enrolling patients with metastatic breast cancer in the US and Europe. Two of these
2.3 Initial clinical experience
studies investigate the efficacy of ertumaxomab in patients
First in vivo
investigations were performed by Heiss et al.
with an HER2/neu expression of 1+ or 2+ (IHC), FISH
demonstrating the elimination of autologous tumour cells
negative, with disease progression after adequate endocrine
after intraperitoneal application of ertumaxomab in patients
therapy. Differing from the Phase I approach with only
three infusions, one of the studies extends treatment up to
(one patient with breast cancer and two patients with 12 weekly administrations regardless of HAMA status. The ovarian cancer) were treated with ertumaxomab in combination
third study investigates three weekly administrations of
with another trifunctional antibody, catumaxomab (Fresenius
ertumaxomab in HER2/neu overexpressing patients after
Biotech/Trion Pharma, Munich, Germany), binding EpCAM
and CD3, and one patient with breast cancer received only ertumaxomab. A significant reduction or elimination
of HER2 positive tumour cells in the ascites measured by flow cytometry was seen under therapy in all patients, So far, the HER2/neu and CD3 targeting bispecific antibody along with a reduction or disappearance of ascites and ertumaxomab has shown promising activity in preclinical ascites-related symptoms.
models including HER2/neu low-expressing cell lines. The trifunctionality of action involving T cells and accessory
3. Ertumaxomab for breast cancer treatment
immune cells may result in a more potent tumour cell killing compared with available anti-HER2/neu directed
3.1 Clinical data
agents at present. Clinical experience is thus far limited to a
Thus, far, clinical data on systemic treatment with Phase I trial showing a strong immune response with ertumaxomab are limited to a Phase I study of 17 metastatic
manageable cytokine-release associated toxicity and first
breast cancer patients with intravenous administration of
evidence of antitumour activity. Several Phase II trials are
three ascending doses and a weekly interval
now continuing to evaluate clinical efficacy in HER2/neu
maximum tolerated single dose was identified at 100 µg.
low-expressing breast cancer and patients resistant to
Toxicity was mostly related to cytokine release, including
fever (94% of patients), rigors (47%), headache (35%), nausea (29%) and vomiting (29%). Less frequently, pain,
5. Expert opinion
arthralgia, dyspnea or hypertension was observed. Three patients treated at dose levels above the maximum tolerated
Bispecific antibodies are promising candidates for the
single dose showed severe reactions: one patient suffered
targeted treatment of human cancer. Simultaneous binding
from respiratory distress syndrome and hypotension, another
to tumour antigens and immune cells may yield an enhanced
patient developed a systemic inflammatory response immune reaction and more effective tumour cell killing as syndrome with acute renal failure and a third patient had
compared with the moderate response rates seen in
Expert Opin. Investig. Drugs
monoclonal antibody treatment with single binding whether these antibodies may have a neutralising effect specificity. Ertumaxomab represents a novel development in
on subsequent BsAb application, leaving only a narrow
BsAb manufacture owing to its chimeric Fc portion with
therapeutic window. This may limit chances of an ‘immune
γ type I/III-receptors. The boost’ effect by repeated BsAb infusion cycles, which may be
proposed trifunctional mode of action involving antibody-
crucial for the successful development of long-lasting tumour
dependent cell-mediated cytotoxicity, T-cell activation and
immunity. Therefore, the optimal dosing schedule remains
the recruitment of accessory immune cells could be the key
to be clarified. The current Phase II studies with extended
to overcome immune escape mechanisms and to induce
ertumaxomab applications will have to evaluate the effect of
neutralising antibodies as well as to provide data on adaptive
Another trifunctional antibody with a similar mode of
action, catumaxomab, has recently shown encouraging
HER2/neu directed immunotherapy in patients without
activity in a randomised Phase II/III study of intraperitoneal
gene amplification remains an attractive yet ambivalent issue.
catumaxomab application versus best supportive care in The dual tyrosine kinase inhibitor lapatinib for instance patients suffering from malignant ascites  . Most frequent
showed preclinical activity in a HER2/neu negative, EGFR
side effects in this study included profound but transient
positive cell line that did not translate into clinical efficacy
elevation of liver enzymes and symptoms related to for this group of patients, underscoring the importance of cytokine release.
HER2/neu overexpression in breast cancer biology
The experience with catumaxomab and preliminary data
However, lapatinib inhibits intracellular receptor signalling
on ertumaxomab activity are particularly remarkable because,
and does not involve the immune system. For the treatment
thus far, BsAb have not matched their potent in vitro
of breast cancer with HER2/neu overexpression, accounting
lysis properties in the clinical setting.
for approximately a quarter of patients, trastuzumab and
One of the most attractive effects of a treatment with
lapatinib have firmly emerged as the standard of care and
trifunctional antibodies could be the induction of a durable
moved forward to the adjuvant treatment of early breast
adaptive immune response. Long-lasting tumour immunity
cancer. Therefore, it will be very difficult for any new
could promote longer disease-free survival after initial HER2/neu directed treatment to advance through clinical cytoreduction or control minimal residual disease in a (neo-)
trials and show superiority over those well established
adjuvant setting. In theory, the proximity of tumour cells to
therapies. Furthermore, various new compounds are in line
accessory immune cells results in phagocytosis, subsequent
to be used for the emerging field of trastuzumab resistance
human leukocyte antigen–unrestricted antigen processing such as trastuzumab drug-conjugates, that is, trastuzumab-and extracellular presentation of the target antigen and DM1 or HER dimerisation inhibitors, that is, pertuzumab. other immunogenic tumour-associated antigens. Proof of
Even for those patients without HER2/neu overexpression
this concept has been reported from an immunocompetent
and those with further absence of hormone receptors –
syngeneic mouse tumour model with antibodies targeting
a disease entity recently attributed to a particularly poor
prognosis – numerous newly developed biological agents
adaptive humoral and cellular immune responses have been
and conventional cytostatic drugs are in advanced clinical
found in breast cancer patients treated with 2B1, a murine
development. Among these are agents targeting angiogenesis,
monoclonal BsAb targeting HER2/neu and Fc γ RIIIA  .
that is, bevacizumab; multi-targeted tyrosine kinase
The strength of induced immune responses after inhibitors, that is, sunitinib and chemotherapeutic agents,
systemic treatment with ertumaxomab visualised by the that is, epothilones. reported cyto kine release raises safety concerns. Two patients
It will be very difficult for any new drug development to
experienced severe inflammatory response syndromes after
compete in an area of great public and commercial interest
treatment with ertumaxomab within the Phase I study. that is well developed by clinical trials. Ertumaxomab will Treatment with BsAb 2B1 targeting HER2/neu and Fc γ RIII
need to show convincing Phase II data with regard to clinical
(CD16) also revealed substantial cytokine-release associated
efficacy and immunological surrogates and define its
toxicity and dose-limiting thrombocytopenia at a dose of
therapeutic niche. The proposed mode of action suggests
that it can be a potent agent to overcome trastuzumab
BIS-1, a BsAb directed against tumour-associated antigen
resistance and to induce long-lasting immunity.
EGP-2 and CD3  . Another issue is the development of HAMA or HARA observed in a third of patients after three
Declaration of interest
infusions of ertumaxomab and all patients after five consecutive daily infusions of 2B1 [30,34] . Even in the absence
P Kiewe has received research grants and honoraria from
of HAMA/HARA-related toxicity, the question remains Fresenius Biotech.
Expert Opin. Investig. Drugs
Kiewe & Thiel
Repp R, van Ojik HH, Valerius T, et al.
Papers of special note have been highlighted
Phase I clinical trial of the bispecifi c
as either of interest (•) or of considerable
Registration trial leading to the
approval of lapatinib for HER2/neu
positive breast cancer.
Revillion F, Bonneterre J, Peyrat JP. ErbB-2
et al. Effi cacy and safety of lapatinib as
fi rst-line therapy for ErbB2-amplifi ed
locally advanced or metastatic breast cancer.
Thierfelder S. Preferential species-restricted
quadromas. Implications for a single-step
relapse and survival with amplifi cation
purifi cation of bispecifi c antibodies.
et al. Effi cacy and safety of trastuzumab
as a single agent in fi rst-line treatment of
Describes the production of bispecifi c
Milestone paper reporting on the
antibodies with trifunctional properties.
adverse prognostic impact of HER2/neu
cancer. J Clin Oncol 2002 ; 20 : 719 -26
in breast cancer.
Zeidler R, Mysliwietz J, Csanady M, et al. The Fc-region of a new class of
biomarker profi les for response targeting
activation of accessory cells and NK cells
human epidermal growth factor receptor 2
and induces direct phagocytosis of tumor
(HER-2) in advanced infl ammatory breast cancer with lapatinib monotherapy.
et al. Simultaneous activation of T-cells
prognosis in breast cancer. J Clin Oncol
Burstein HJ, Storniolo AM, Franco S, et al.
A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive
and HER2-negative advanced or metastatic
effi cient tumor cell killing. J Immunol
et al. Multinational study of the effi cacy
Specifi c targeting of cytotoxic T cells by
anti-T3 linked to anti-target cell antibody.
First report on concurrent targeting of
T cells and tumour antigens.
Schauwecker P, et al. Adoptive therapy of
metastatic breast cancer that overexpresses
Going both ways: bispecifi c antibodies and
with antibody coated immune cells: a pilot
clinical trial. Cancer Immunol Immunother
Defi ning a new standard of care
in the treatment of HER2/neu
positive metastatic breast cancer.
Jäger M, Ruf P, Schoberth A, et al. Effect on low HER2 (1+) expressing tumor cells
of the trifunctional antibody ertumaxomab
Valerius T, Stockmeyer B, van Spriel AB,
et al. FcalphaRI (CD89) as a novel trigger
Leidig T, Wawrsinek F, Lindemann C, Mueller-Klieser W. The trifunctional
molecule for bispecifi c antibody therapy.
for operable HER2-positive breast cancer.
for Cancer Research; 12 – 16 April 2008 ;
et al. Construction of optimized bispecifi c
antibodies for selective activation of the
Lindhofer H, Menzel H, Zengerle U, et al.
Bispecifi c antibodies effectively purge
Expert Opin. Investig. Drugs
intravenous treatment of carcinoma patients:
cell collections without affecting colony
forming units. Exp Hematol 1997 ; 25 : 879
by a trifunctional bispecifi c antibody.
Kiewe P, Hasmüller S, Kahlert S, et al.
Phase I trial of the trifunctional anti-HER2
Provides evidence that adaptive
et al. The characterization of novel, dual
immunity can be induced by a
ErbB-2/EGFR, tyrosine kinase inhibitors:
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potential therapy for cancer. Cancer Res
Borghaei H, Alpaugh RK, Bernardo P, et al.
Heiss MM, Strohlein MA, Jäger M, et al.
et al. Phase I trial of 2B1, a bispecifi c
Provides fi nal results of the fi rst
registration trial of the bispecifi c
antibody: the use of ertumaxomab
Kroesen BJ, Janssen RA, Buter J, et al.
for the treatment of malignant ascites.
Expert Opin. Investig. Drugs
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