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Schmidt M.,Johannes Gutenberg University Mainz | Scheulen M.E.,University of Duisburg - Essen | Dittrich C.,Institution for Translational Research Vienna | Dittrich C.,Ludwig Boltzmann Research Institute | And 8 more authors.
Annals of Oncology | Year: 2010

Background: High-level expression of epithelial cell adhesion molecule (EpCAM) is associated with unfavorable prognosis in breast cancer. This study was designed to investigate two doses of the fully human IgG1 anti-EpCAM antibody adecatumumab (MT201) in patients with metastatic breast cancer (MBC). Methods: A total of 109 patients were stratified into high- and low-level EpCAM expression by immunohistochemical staining of primary tumors and subsequently randomly assigned to receive monotherapy with either high- (6 mg/kg every two weeks (q2w)) or low-dose adecatumumab (2 mg/kg/q2w) until disease progression. Results: No complete or partial tumor responses could be confirmed by central RECIST assessment. The probability for tumor progression was significantly lower in patients receiving high-dose adecatumumab and expressing high levels of EpCAM (hazard ratio 0.43; P = 0.0057 versus low dose and low EpCAM). Three of 18 patients with highest EpCAM expression treated with adecatumumab developed new metastases up to week 6, compared with 14 of 29 patients with low EpCAM. Most frequent treatment-related adverse events (high dose/low dose) were chills (59%/20%), nausea (55%/18%), fatigue (39%/23%) and diarrhea (43%/7%). Conclusions: Single-agent adecatumumab shows dose- and target-dependent clinical activity in EpCAM-positive MBC, albeit no objective tumor regression. Further investigation of adecatumumab in patients with EpCAMoverexpressing tumors and lower tumor burden is warranted. © The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Ruttinger D.,Ludwig Maximilians University of Munich | Ruttinger D.,Micromet AG | Winter H.,Ludwig Maximilians University of Munich | Van Den Engel N.K.,Ludwig Maximilians University of Munich | And 4 more authors.
Oncologist | Year: 2010

Cancer immunotherapy broadly includes active immunization, as in the use of cancer vaccines, passive immunization, such as the use of adoptive cell therapy and antibodies that modulate tumor function, and immunostimulation, using antibodies and small molecules to treat malignancy by activating or unleashing an endogenous immune response against tumor cells. Currently, > 100 different monoclonal antibodies are in use or under evaluation for use as therapeutic agents in various malignancies. Active stimulation of the host's immune system holds promise for achieving durable remission of malignant disease and represents a nontoxic method of therapy if tumor-specific effector cells can be selectively targeted. However, no active-specific treatment strategy (i.e., a therapeutic cancer vaccine) has yet found its way into the clinical armamentarium, although several promising recent reports suggest that, for follicular lymphoma, prostate cancer, and melanoma, clinical benefit was shown for the first time in randomized trials with a vaccine approach. Here, we report on the key findings of the Third Tegernsee Conference on Immunotherapy of Cancer (Feldafing, Germany, July 2-4, 2009) and provide short commentaries on data presented at this meeting regarding the future role of cancer vaccines, recent developments in adoptive cellular therapy, ways to improve immunotherapeutic treatment modalities (e.g., by manipulating the tumor microenvironment), and some novel targeted therapies that are well advanced in clinical testing, all of which have implications for future oncology practice. ©AlphaMed Press.


Bluemel C.,Micromet AG | Hausmann S.,Micromet AG | Fluhr P.,Micromet AG | Sriskandarajah M.,Micromet AG | And 4 more authors.
Cancer Immunology, Immunotherapy | Year: 2010

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. © 2010 Springer-Verlag.


Patent
Micromet Ag and Medimmune Llc | Date: 2011-07-18

The present disclosure provides compositions and methods for treating CEA-expressing cancers. Methods for dosing a patient with an antibody that binds to CEA and human CD3 are also provided.


Patent
Micromet AG | Date: 2013-01-14

The present disclosure relates to a bispecific single chain antibody which has a first binding domain specifically binding to human CD3, and a second binding domain specifically binding to human CEA, where the second binding domain comprises at least a part of the CDR-H3 or the complete CDR-H3 of murine monoclonal antibody A5B7, a pharmaceutical composition comprising the bispecific single chain antibody, and methods for the treatment of an epithelial tumor in a human with the pharmaceutical compositions containing the bispecific single chain antibody. Furthermore, processes for the production of the pharmaceutical compositions as well as medical/pharmaceutical uses for the specific bispecific single chain antibody molecules bearing specificities for the human CD3 antigen and the human CEA antigen are disclosed.


Patent
Micromet AG | Date: 2011-03-09

The present invention provides a cytotoxically active CD3 specific binding construct comprising a first domain specifically binding to human CD3 and an Ig-derived second binding domain. Furthermore, a nucleic acid sequence encoding a CD3 specific binding construct of the invention is provided. Further aspects of the invention are vectors and host cells comprising said nucleic acid sequence, a process for the production of the construct of the invention and composition comprising said construct. The invention also provides the use of said constructs for the preparation of pharmaceutical compositions for the treatment of particular diseases, a method for the treatment of particular diseases and a kit comprising the binding construct of the invention.


The present invention relates to a human monoclonal antibody or fragment thereof which specifically binds to and neutralizes primate GM-CSF.


The present invention relates to a human monoclonal antibody or fragment thereof which specifically binds to and neutralizes primate GM-CSF.


Patent
Micromet Ag | Date: 2011-07-11

The present invention relates to the use of an anti-EpCAM antibody for the manufacture of a medicament for the treatment of metastatic breast cancer. The present invention further relates to a method of treating metastatic breast cancer comprising administering said anti-EpCAM antibody.


Patent
Micromet AG | Date: 2010-05-19

The present invention relates to compositions comprising polypeptides, especially polypeptides capable of specifically binding predetermined antigens. The polypeptide in the composition comprises at least two antigen binding sites. These at least two antigen binding sites are located on a single polypeptide chain. One of the at least two antigen binding sites specifically binds the human CD3 antigen. The polypeptide may exist in both monomeric form and multimeric form. The multimeric form of the polypeptide constitutes no more than 5% of the total weight of the combined monomeric and multimeric forms of said polypeptide.

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