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. Keywords: bispecific antibody , breast cancer , CD3 , HER/2 neu , immunotherapy ,
trifunctional antibody
Expert Opin. Investig. Drugs (2008) 17(10):1553-1558
1. Introduction
EGF family member HER2/neu is overexpressed in tumour specimens of ∼ 25 – 30% of breast cancer patients [1] 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 [6] . 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 [15] , 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 Ertumaxomab
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
trifunctional antibody.
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 ) [23] .
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 models 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 [29] . In vitro the Fc-portion [24] , 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 1554
Expert Opin. Investig. Drugs (2008) 17(10)
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 [30] . Recently, Jäger et al. [27] 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 4. Conclusion
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 (2008) 17(10)
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 [32] . 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 tumour 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 [34] . 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 [36] . 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. 1556
Expert Opin. Investig. Drugs (2008) 17(10)
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
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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 (2008) 17(10)
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: metastatic breast cancer. Clin Cancer Res trifunctional antibody.
potential therapy for cancer. Cancer Res Borghaei H, Alpaugh RK, Bernardo P, et al. Heiss MM, Strohlein MA, Jäger M, et al. Affi liation
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 (2008) 17(10)

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