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Matthias Friedrich,
Tobias Raum,
Ralf Lutterbuese,
Markus Voelkel,
Petra Deegen,
Doris Rau,
Roman Kischel,
Patrick Hoffmann,
Christian Brandl,
Joachim Schuhmacher,
Peter Mueller,
Ricarda Finnern,
Melanie Fuergut,
Dieter Zopf,
Jerry W Slootstra, Patrick A Baeuerle,
Benno Rattel,
Peter Kufer
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ABSTRACT: For treatment of patients with prostate cancer (PCa), we developed a novel T cell-engaging (BiTE) antibody designated MT112 or BAY2010112 that is bispecific for prostate-specific membrane antigen (PSMA) and the CD3 epsilon subunit of the T cell receptor complex. MT112/BAY2010112 induced target cell-dependent activation and cytokine release of T cells, and efficiently redirected T cells for lysis of target cells. In addition to Chinese hamster ovary (CHO) cells stably expressing human or cynomolgus monkey PSMA, T cells redirected by MT112/BAY2010112 also lysed human PCa cell lines VCaP, 22Rv1, MDA PCa 2b, C4-2, PC-3-huPSMA and LnCaP at half maximal BiTE concentrations between 0.1 and 4 ng/ml (1.8-72 pM). No lysis of human PCa cell lines PC-3 and DU145, which do not express PSMA, was observed. The subcutaneous (s.c.) formation of tumors from PC-3-huPSMA cells in NOD/SCID mice was significantly prevented by once daily intravenous (i.v.) injection of MT112/BAY2010112 at a dose level as low as 0.005 mg/kg/d. Rapid tumor shrinkage with complete remissions were observed in NOD/SCID mice bearing established s.c. 22Rv1 xenografts after repeated daily treatment with MT112/BAY2010112 by either the i.v. or s.c. route. Of note, 22Rv1 tumors were grown in the absence of human T cells followed by intraperitoneal injection of T cells three days prior to BiTE treatment. No effects on tumor growth were observed in the absence of human T cells or MT112/BAY2010112. Based on these preclinical results, MT112/BAY2010112 appears as a promising new BiTE antibody for the treatment of patients with PSMA-expressing PCa.
Molecular Cancer Therapeutics 10/2012; · 5.23 Impact Factor
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ABSTRACT: For decades, chemotherapy has been the backbone for the treatment of patients with B cell malignancies. Depending on the individual disease, monoclonal antibodies, irradiation and/or hematopoietic stem cell transplantation are added. However, the current standard of care - particularly for patients with relapsed disease - is often not sufficient to achieve durable remissions. A highly promising new drug candidate in late-stage clinical development for treatment of B cell malignancies is blinatumomab (MT103 or AMG 103). This bispecific antibody construct has dual specificity for CD19 and CD3 and belongs to the class of bispecific T cell engager (BiTE®) antibodies, which can potentially engage all cytotoxic T cells of a patient for redirected lysis of tumor cells. Here, we review how blinatumomab has so far been pre-clinically and clinically developed for the treatment of patients with non-Hodgkin's lymphoma and acute lymphoblastic leukemia.
Pharmacology [?] Therapeutics 08/2012; · 8.56 Impact Factor
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ABSTRACT: Unlike any other cell type, T cells have a unique potential to eliminate cancer cells and to eventually cure cancer patients. As a result, researchers have made extensive efforts over the past three decades to develop therapeutics with the potential to mount T cell responses against cancer cells. One way in which such T cell responses can be triggered is by vaccines and adjuvants, potentially leading to tumor-specific T cell clones and lasting immunity. Alternatively, they can be induced with the help of recombinant proteins that either are expressed in patients’ T cells by gene therapeutic means, or are delivered to patients as pharmaceuticals for temporary engagement of T cells. With both recombinant technologies, cytotoxic T cells can be engaged for cancer cell lysis regardless of T cell receptor specificity and with the prospect of bypassing both complex T cell regulation and frequent immune escape mechanisms of tumor cells. In this review, we will focus on recombinant approaches for T cell engagement that currently are in clinical development. Approaches transfecting patient T cells with genes encoding recombinant T cell receptors or antibody fusion proteins will be compared to those temporarily engaging T cells by infused recombinant bispecific proteins. Initial experience has recently been gained in the clinic with both technologies such that their fundamental differences can now be discussed on the basis of patient data.
Current pharmaceutical biotechnology 06/2012; 13(8):1399-408. · 3.40 Impact Factor
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Matthias Klinger,
Christian Brandl,
Gerhard Zugmaier,
Youssef Hijazi,
Ralf C Bargou,
Max S Topp,
Nicola Gökbuget,
Svenja Neumann,
Mariele Goebeler,
Andreas Viardot,
Matthias Stelljes,
Monika Brüggemann,
Dieter Hoelzer,
Evelyn Degenhard,
Dirk Nagorsen, Patrick A Baeuerle,
Andreas Wolf,
Peter Kufer
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ABSTRACT: T cell-engaging CD19/CD3-bispecific BiTE Ab blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD(+) B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B-cell counts dropped to < 1 B cell/μL within an average of 2 days and remained essentially undetectable for the entire treatment period. By contrast, T-cell counts in all patients declined to a nadir within < 1 day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline within 2-3 weeks under continued infusion of blinatumomab. A significant percentage of reappearing CD8(+) and CD4(+) T cells newly expressed activation marker CD69. Shortly after start of infusion, a transient release of cytokines dominated by IL-10, IL-6, and IFN-γ was observed, which no longer occurred on start of a second treatment cycle. The response of lymphocytes in leukemic patients to continuous infusion of blinatumomab helps to better understand the mode of action of this and other globally T cell-engaging Abs. The trial is registered with www.clinicaltrials.gov identifier NCT00560794.
Blood 05/2012; 119(26):6226-33. · 9.90 Impact Factor
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ABSTRACT: Melanoma-associated chondroitin sulfate proteoglycan (MCSP; also called HMW-MAA, CSPG4, NG2, MSK16, MCSPG, MEL-CSPG, or gp240) is a well characterized melanoma cell-surface antigen. In this study, a new bispecific T-cell engaging (BiTE) antibody that binds to MCSP and human CD3 (MCSP-BiTE) was tested for its cytotoxic activity against human melanoma cell lines. When unstimulated peripheral mononuclear blood cells (PBMCs) derived from healthy donors were cocultured with melanoma cells at effector:target ratios of 1:1, 1:5, or 1:10, and treated with MCSP-BiTE antibody at doses of 10, 100, or 1000 ng/mL, all MCSP-expressing melanoma cell lines (n=23) were lysed in a dose-dependent and effector:target ratio-dependent manner, whereas there was no cytotoxic activity against MCSP-negative melanoma cell lines (n=2). To investigate whether T cells from melanoma patients could act as effector cells, we cocultured unstimulated PBMCs with allogeneic melanoma cells from 13 patients (4 stage I/II, 3 stage III, and 6 stage IV) or with autologous melanoma cells from 2 patients (stage IV). Although cytotoxic activity varied, all 15 PBMC samples mediated significant redirected lysis by the BiTE antibody. When PBMC or CD8 T cells were prestimulated by anti-CD3 antibody OKT-3 and interleukin-2, the MCSP-BiTE concentrations needed for melanoma cell lysis decreased up to 1000-fold. As MCSP is expressed on most human melanomas, immunotherapy with MCSP/CD3-bispecific antibodies merits clinical investigation.
Journal of immunotherapy (Hagerstown, Md.: 1997) 09/2011; 34(8):597-605. · 3.20 Impact Factor
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Christine Plater-Zyberk,
Dave M Lopes Estêvão,
Sandrine d'Argouges,
Krista G Haanstra,
Ivanela Kondova,
Michel Vierboom,
Thomas Boehm,
Ruediger Neef,
Eva M Vieser,
Benno Rattel, Patrick A Baeuerle,
Margeet Jonker
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ABSTRACT: MT204 is a humanized IgG1 antibody specific for interleukin-2 (IL-2) of human and rhesus monkey origin. It potently antagonizes IL-2 signaling in both CD25(+) and CD25(-) cells by a unique mode of action. MT204 can not only prevent soluble IL-2 from binding to the intermediate affinity IL-2 receptors but can also antagonize IL-2 that is already bound to the CD25 subunit of high affinity IL-2 receptors on the cell surface. As initial steps toward development of a therapeutic antibody, pharmacokinetics (PK) and tolerability of MT204, as well as efficacy were investigated in rhesus monkeys. MT204 was infused by single escalating (2, 10 and 50mg/kg) or repeat dose administrations (50mg/kg, 1 ×/week for 3 weeks). Over the course of the experiment, the animals were regularly observed for clinical adverse reaction and bled for laboratory investigations (PK, hematology, chemical chemistry and leukocyte subset analysis). For the efficacy study, six rhesus monkeys were grafted with MHC-mismatched rhesus skin and infused with MT204 (50mg/kg), on the day of transplantation and again on days 5 and 12 post grafting. Efficacy was determined by assessment of graft necrosis at different time-points. No obvious adverse effects were observed clinically after single infusion, or after three repeated infusions of 50mg/kg and no MT204-related toxic effects were revealed by hematology or clinical chemistry. In the efficacy study, MT204-treated animals showed a significant delay in graft rejection versus control animals (p=0.025 by Log-rank test). The characteristics of MT204, displaying linear pharmacokinetics, half-life in the range expected for a human IgG, benign safety profile and signs of efficacy, warrant further development of this antibody for therapy.
Transplant Immunology 06/2011; 25(2-3):133-40. · 1.46 Impact Factor
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Max S Topp,
Peter Kufer,
Nicola Gökbuget,
Mariele Goebeler,
Matthias Klinger,
Svenja Neumann,
Heinz-A Horst,
Thorsten Raff,
Andreas Viardot,
Mathias Schmid, [......],
Margit Schmidt,
Ralf Lutterbuese,
Carsten Reinhardt, Patrick A Baeuerle,
Michael Kneba,
Hermann Einsele,
Gert Riethmüller,
Dieter Hoelzer,
Gerhard Zugmaier,
Ralf C Bargou
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ABSTRACT: Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.
Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours.
Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events.
Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.
Journal of Clinical Oncology 06/2011; 29(18):2493-8. · 18.37 Impact Factor
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ABSTRACT: Severe side effects and few long-term remissions frequently limit the treatment of advanced malignant diseases. Bispecific antibodies are currently emerging as a new option for the treatment of malignant diseases, which can potentially engage all cytotoxic T cells of a patient for tumor cell lysis. Blinatumomab, a bispecific single-chain BiTE antibody construct with dual specificity for CD19 and CD3, is a front runner of this antibody class. We here summarize the current state of development of blinatumomab for the treatment of patients with B-cell non-Hodgkin's lymphoma (NHL) and B-precursor acute lymphocytic leukemia (ALL). High response rates and durable remissions are observed in first clinical trials, indicating that T cells can be potently redirected for efficient and lasting elimination of malignant cells.
Experimental Cell Research 03/2011; 317(9):1255-60. · 3.58 Impact Factor
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Markus Münz,
Alexander Murr,
Majk Kvesic,
Doris Rau,
Susanne Mangold,
Stefan Pflanz,
John Lumsden,
Jörg Volkland,
Jan Fagerberg,
Gert Riethmüller,
Dominik Rüttinger,
Peter Kufer, Patrick A Baeuerle,
Tobias Raum
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ABSTRACT: Epithelial cell adhesion molecule (EpCAM) is frequently and highly expressed on human carcinomas. The emerging role of EpCAM as a signalling receptor and activator of the wnt pathway, and its expression on tumor-initiating cells, further add to its attractiveness as target for immunotherapy of cancer. Thus far, five conventional monoclonal IgG antibodies have been tested in cancer patients. These are murine IgG2a edrecolomab and its murine/human chimeric IgG1 antibody version, and humanized, human-engineered and fully human IgG1 antibodies 3622W94, ING-1, and adecatumumab (MT201), respectively. Here we compared all anti-EpCAM antibodies in an attempt to explain differences in clinical activity and safety.
We recombinantly produced all antibodies but murine edrecolomab and investigated them for binding affinity, EpCAM epitope recognition, ADCC and CDC, and inhibition of breast cancer cell proliferation.
ING-1 and 3622W94 bound to EpCAM with much higher affinity than adecatumumab and edrecolomab. Edrecolomab, ING-1, and 3622W94 all recognized epitopes in the exon 2-encoded N-terminal domain of EpCAM, while adecatumumab recognized a more membrane proximal epitope encoded by exon 5. All antibodies induced lysis of EpCAM-expressing cancer cell lines by both ADCC and CDC with potencies that correlated with their binding affinities. The chimeric version of edrecolomab with a human Fcγ1 domain was much more potent in ADCC than the murine IgG2a version. Only adecatumumab showed a significant inhibition of MCF-7 breast cancer cell proliferation in the absence of complement and immune cells.
A moderate binding affinity and recognition of a distinct domain of EpCAM may best explain why adecatumumab showed a larger therapeutic window in cancer patients than the two high-affinity IgG1 antibodies ING-1 and 3622W94, both of which caused acute pancreatitis.
Cancer Cell International 11/2010; 10:44. · 1.97 Impact Factor
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Ralf Lutterbuese,
Tobias Raum,
Roman Kischel,
Patrick Hoffmann,
Susanne Mangold,
Benno Rattel,
Matthias Friedrich,
Oliver Thomas,
Grit Lorenczewski,
Doris Rau,
Evelyne Schaller,
Ines Herrmann,
Andreas Wolf,
Thomas Urbig, Patrick A Baeuerle,
Peter Kufer
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ABSTRACT: Epidermal growth factor receptor (EGFR)-specific monoclonal antibodies predominantly inhibit colorectal cancer (CRC) growth by interfering with receptor signaling. Recent analyses have shown that patients with CRC with mutated KRAS and BRAF oncogenes do not profit from treatment with such antibodies. Here we have used the binding domains of cetuximab and pantitumumab for constructing T cell-engaging BiTE antibodies. Both EGFR-specific BiTE antibodies mediated potent redirected lysis of KRAS- and BRAF-mutated CRC lines by human T cells at subpicomolar concentrations. The cetuximab-based BiTE antibody also prevented at very low doses growth of tumors from KRAS- and BRAF-mutated human CRC xenografts, whereas cetuximab was not effective. In nonhuman primates, no significant adverse events were observed during treatment for 3 wk at BiTE serum concentrations inducing, within 1 d, complete lysis of EGFR-overexpressing cancer cells. EGFR-specific BiTE antibodies may have potential to treat CRC that does not respond to conventional antibodies.
Proceedings of the National Academy of Sciences 07/2010; 107(28):12605-10. · 9.68 Impact Factor
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Journal of Clinical Oncology 04/2010; 28(15):e239-40; author reply e241-2. · 18.37 Impact Factor
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ABSTRACT: Melanoma chondroitin sulfate proteoglycan (MCSP; also called CSPG4, NG2, HMW-MAA, MSK16, MCSPG, MEL-CSPG, or gp240) is a surface antigen frequently expressed on human melanoma cells, which is involved in cell adhesion, invasion and spreading, angiogenesis, complement inhibition, and signaling. MCSP has therefore been frequently selected as target antigen for development of antibody- and vaccine-based therapeutic approaches. We have here used a large panel of monoclonal antibodies against human MCSP for generation of single-chain MCSP/CD3-bispecific antibodies of the BiTE (for bispecific T cell engager) class. Despite similar binding affinity to MCSP, respective BiTE antibodies greatly differed in their potency of redirected lysis of CHO cells stably transfected with full-length human MCSP, or with various MCSP deletion mutants and fusion proteins. BiTE antibodies binding to the membrane proximal domain D3 of MCSP were more potent than those binding to more distal domains. This epitope distance effect was corroborated with EpCAM/CD3-bispecific BiTE antibody MT110 by testing various fusion proteins between MCSP and EpCAM as surface antigens. CHO cells expressing small surface target antigens were generally better lysed than those expressing larger target antigens, indicating that antigen size was also an important determinant for the potency of BiTE antibody. The present study for the first time relates the positioning of binding domains and size of surface antigens to the potency of target cell lysis by BiTE-redirected cytotoxic T cells. In case of the MCSP antigen, this provides the basis for selection of a maximally potent BiTE antibody candidate for development of a novel melanoma therapy.
Cancer Immunology and Immunotherapy 03/2010; 59(8):1197-209. · 3.70 Impact Factor
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Norbert Marschner,
Dominik Rüttinger,
Gerhard Zugmaier,
Gyula Nemere,
Jan Lehmann,
Peter Obrist, Patrick A Baeuerle,
Andreas Wolf,
Margit Schmidt,
Per-Anders Abrahamsson,
Carsten Reinhardt,
Axel Heidenreich
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ABSTRACT: Rising serum levels of prostate-specific antigen (PSA) after radical prostatectomy are indicative of recurrent prostate cancer. This double-blind, placebo-controlled phase II study evaluated the anti-tumour activity of the anti-epithelial cell adhesion molecule (EpCAM) antibody adecatumumab in delaying biochemical disease progression.
Prostate cancer patients with increasing serum PSA levels following radical prostatectomy were randomized to low- (2 mg/kg) or high-dose adecatumumab (6 mg/kg) or placebo. The primary efficacy endpoint was the mean change from baseline in total serum PSA at week 24. Secondary endpoints included PSA response rate, prolongation of serum PSA doubling time and time to biochemical disease progression.
The primary and secondary endpoints of the study were not met in the predefined analyses. In a retrospective analysis of patients with baseline PSA ≤ 1 ng/ml and a high EpCAM expression, both the mean increase in PSA from baseline to week 24 and the PSA doubling time at week 15 were significantly improved in the high-dose adecatumumab group compared with the placebo group. Most frequent treatment-related clinical adverse events were gastrointestinal (diarrhoea and nausea) or general events (chills), showing a dose dependency but no grade 3/4 intensity in any patient.
In men with rising PSA levels after radical prostatectomy and no evidence of clinical relapse, adecatumumab delayed disease progression in a subgroup of patients with baseline PSA levels ≤ 1 ng/ml and high EpCAM-expressing tumours.
Urologia Internationalis 01/2010; 85(4):386-95. · 0.99 Impact Factor
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Ines Herrmann, Patrick A Baeuerle,
Matthias Friedrich,
Alexander Murr,
Susanne Filusch,
Dominik Rüttinger,
Mariam W Majdoub,
Sherven Sharma,
Peter Kufer,
Tobias Raum,
Markus Münz
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ABSTRACT: With their resistance to genotoxic and anti-proliferative drugs and potential to grow tumors and metastases from very few cells, cancer stem or tumor-initiating cells (TICs) are a severe limitation for the treatment of cancer by conventional therapies. Here, we explored whether human T cells that are redirected via an EpCAM/CD3-bispecific antibody called MT110 can lyse colorectal TICs and prevent tumor growth from TICs. MT110 recognizes EpCAM, a cell adhesion molecule expressed on TICs from diverse human carcinoma, which was recently shown to promote tumor growth through engagement of elements of the wnt pathway. MT110 was highly potent in mediating complete redirected lysis of KRAS-, PI3 kinase- and BRAF-mutated colorectal TICs, as demonstrated in a soft agar assay. In immunodeficient mice, MT110 prevented growth of tumors from a 5,000-fold excess of a minimally tumorigenic TIC dose. T cells engaged by MT110 may provide a potent therapeutic means to eradicate TICs and bulk tumor cells derived thereof.
PLoS ONE 01/2010; 5(10):e13474. · 4.09 Impact Factor
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10/2009: pages 179 - 200; , ISBN: 9783527625970
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ABSTRACT: Initially discovered as a dominant antigen on colon carcinomas, the epithelial cell adhesion molecule (EpCAM) was considered a mere cell adhesion molecule and reliable surface-binding site for therapeutic antibodies. Recent findings can better explain the relevance of EpCAM's high-level expression on human cancers and cancer propagating cells, and its negative prognostic potential for survival of patients with certain cancers. EpCAM has oncogenic potential and is activated by release of its intracellular domain, which can signal into the cell nucleus by engagement of elements of the wnt pathway.
Cancer Research 08/2009; 69(14):5627-9. · 7.86 Impact Factor
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ABSTRACT: There is increasing evidence that T cells are able to control tumor growth and survival in cancer patients, both in early and late stages of the disease. However, tumor-specific T-cell responses are difficult to mount and sustain in cancer patients, and are limited by numerous immune escape mechanisms of tumor cells selected during immunoediting. An alternative approach to engage T cells for cancer therapy are antibodies, which are bispecific for a surface target antigen on cancer cells, and for CD3 on T cells. These are capable of connecting any kind of cytotoxic T cell to a cancer cell, independently of T-cell receptor specificity, costimulation, or peptide antigen presentation. Here, we review the principle of a new class of bispecific antibodies called BiTE (for "bispecific T-cell engager") antibodies. Recent results from clinical studies with a CD19/CD3-bispecific BiTE antibody suggest that this therapeutic paradigm is finally showing promise for treatment of both bulky and minimal residual disease.
Cancer Research 07/2009; 69(12):4941-4. · 7.86 Impact Factor
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Maria Amann,
Sandrine D'Argouges,
Grit Lorenczewski,
Klaus Brischwein,
Roman Kischel,
Ralf Lutterbuese,
Susanne Mangold,
Doris Rau,
Jörg Volkland,
Stefan Pflanz,
Tobias Raum,
Markus Münz,
Peter Kufer,
Bernd Schlereth, Patrick A Baeuerle,
Matthias Friedrich
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ABSTRACT: muS110 is a BiTE antibody bispecific for murine EpCAM (CD326) and murine CD3. MT110, its human-specific analog, is in a clinical phase 1 trial for treatment of patients with adenocarcinoma of the lung or gastrointestinal tract. Recent studies have shown a therapeutic window for muS110, have explored single-dose toxicity of muS110, and have found that a 1-week low-dose treatment dramatically increased the tolerability of mice to very high doses of muS110 (Cancer Immunol. Immunother. 2009;58:95-109). Here we analyzed the impact of long-term, high-dose treatment of mice with muS110 on antitumor activity and functionality of T cells. After an initial self-limiting cytokine release, the 1-week adaptation period effectively blunted further cytokine production in response to a subsequent high-dose treatment with muS110. The much-increased tolerability of mice adapted to muS110 was not because of anergy of T cells. T cells isolated from chronically muS110-treated mice fully retained their cytotoxic potential, proliferative capacity, and responsiveness to stimulation by either muS110 or anti-CD3/anti-CD28/interleukin-2 when compared with T cells from control mice. Unimpaired T-cell performance was also evident from the effective prevention of orthotopic 4T1 breast tumor outgrowth in mice treated long term with escalating doses of muS110. Finally, we show that muS110 and MT110 recognize orthologous epitopes on mouse and human EpCAM proteins, suggesting that the target-related safety profile of muS110 in mice may be predictive for MT110 in humans.
Journal of immunotherapy (Hagerstown, Md.: 1997) 07/2009; 32(5):452-64. · 3.20 Impact Factor
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ABSTRACT: Bispecific T-cell-engager (BiTE) antibodies are designed to transiently engage cytotoxic T-cells for lysis of selected target cells. Although this therapeutic concept had been proposed more than two decades ago, BiTE, and also trispecific, antibodies did not achieve clinical proof-of-concept until the past 2 years. Their clinical activity corroborates findings that ex vivo expanded, autologous T-cells derived from tumor tissue, or transfected with specific T-cell receptors, have shown therapeutic potential in the treatment of solid tumors. While these personalized approaches prove that T-cells alone can have considerable therapeutic activity, even in late-stage cancer, they are cumbersome to perform on a broad basis. This is different for cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies, which facilitate generation of tumor-specific T-cell clones, and also for bi- and tri-specific antibodies that directly engage a large proportion of patients' T-cells for cancer cell lysis. The potential of global T-cell engagement for human cancer therapy by T-cell-engaging antibodies has yet to be fully investigated.
Current opinion in molecular therapeutics 03/2009; 11(1):22-30. · 3.68 Impact Factor
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ABSTRACT: MT110 is an EpCAM/CD3-bispecific antibody construct in clinical development for the treatment of patients with adenocarcinoma expressing EpCAM (CD326). Like other members of this antibody class, MT110 can engage resting, polyclonal CD8(+) and CD4(+) T cells for highly potent redirected lysis of target cells. Here we further explored the mechanism of this action. Complete lysis of EpCAM(+) Kato III gastric cancer cells by previously unstimulated T cells was achieved within 48 h. During this period, a high percentage of CD4(+) and CD8(+) T cells became activated and increased expression of granzyme B. This apparently boosted the capacity for serial target cell lysis as studied at very low effector-to-target ratios. Elimination of cancer cells by MT110-redirected T cells involved membrane damage as was evident from nuclear uptake of propidium iodide and release of the cytosolic enzyme adenylate kinase. Redirected T cells also potently triggered programmed cell death in cancer cells as was evident by membrane blebbing, activation of procaspases 3 and 7, fragmentation of nuclear DNA and cleavage of the caspase substrate poly (ADP ribose) polymerase. Chelation of extracellular calcium fully protected cancer cells from lysis by MT110-redirected T cells, while the pan-caspase inhibitor Z-VAD-FMK blocked activation of procaspases, cleavage of poly (ADP ribose) polymerase and fragmentation of nuclear DNA in cancer cells, but could not prevent nuclear uptake of propidium iodide. Soluble factors did not significantly contribute to cancer cell death. Our study shows that MT110 can efficiently gear up the potential of CD8(+) and CD4(+) T cells for serial lysis, and mediate kill of cancer cells predominantly through poreforming and pro-apoptotic components of cytotoxic T cell granules.
Immunobiology 02/2009; 214(6):441-53. · 3.20 Impact Factor
