Publications (6)43.62 Total impact
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Article: A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies.
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ABSTRACT: The tetraspanin CD37 is widely expressed in B-cell malignancies and represents an attractive target for immunotherapy with mAbs. We have chimerized a high-affinity mouse Ab to CD37 and engineered the CH2 domain for improved binding to human Fcγ receptors. The resulting mAb 37.1 showed high intrinsic proapoptotic activity on malignant B cells accompanied by homotypic aggregation. Furthermore, the Ab-mediated high Ab-dependent cell-mediated cytotoxicity (ADCC) on lymphoma and primary CLL cells. mAb 37.1 strongly depleted normal B cells as well as spiked B-lymphoma cells in blood samples from healthy donors as well as malignant B cells in blood from CLL patients. In all assays, mAb 37.1 was superior to rituximab in terms of potency and maximal cell lysis. A single dose of mAb CD37.1 administered to human CD37-transgenic mice resulted in a reversible, dose-dependent reduction of peripheral B cells. In a Ramos mouse model of human B-cell lymphoma, administration of mAb 37.1 strongly suppressed tumor growth. Finally, a surrogate Fc-engineered Ab to macaque CD37, with in vitro proapoptotic and ADCC activities very similar to those of mAb 37.1, induced dose-dependent, reversible B-cell depletion in cynomolgus monkeys. In conclusion, the remarkable preclinical pharmacodynamic and antitumor effects of mAb 37.1 warrant clinical development for B-cell malignancies.Blood 07/2011; 118(15):4159-68. · 9.90 Impact Factor -
Article: BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity.
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ABSTRACT: Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To identify novel mitosis-specific agents with higher selectivity than approved tubulin-binding agents (taxanes, Vinca alkaloids), we have generated inhibitors of Polo-like kinase 1, a target that functions predominantly in mitosis. The first compound in this series, suitable for i.v. administration, has entered clinical development. To fully explore the potential of Polo-like kinase 1 inhibition in oncology, we have profiled additional compounds and now describe a novel clinical candidate. BI 6727 is a highly potent (enzyme IC(50) = 0.87 nmol/L, EC(50) = 11-37 nmol/L on a panel of cancer cell lines) and selective dihydropteridinone with distinct properties. First, BI 6727 has a pharmacokinetic profile favoring sustained exposure of tumor tissues with a high volume of distribution and a long terminal half-life in mice (V(ss) = 7.6 L/kg, t(1/2) = 46 h) and rats (V(ss) = 22 L/kg, t(1/2) = 54 h). Second, BI 6727 has physicochemical and pharmacokinetic properties that allow in vivo testing of i.v. as well as oral formulations, adding flexibility to dosing schedules. Finally, BI 6727 shows marked antitumor activity in multiple cancer models, including a model of taxane-resistant colorectal cancer. With oral and i.v. routes of administration, the total weekly dose of BI 6727 is most relevant for efficacy, supporting the use of a variety of well-tolerated dosing schedules. These findings warrant further investigation of BI 6727 as a tailored antimitotic agent; clinical studies have been initiated.Clinical Cancer Research 05/2009; 15(9):3094-102. · 7.74 Impact Factor -
Article: BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo.
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ABSTRACT: Fine-mapping of the cell-division cycle, notably the identification of mitotic kinase signaling pathways, provides novel opportunities for cancer-drug discovery. As a key regulator of multiple steps during mitotic progression across eukaryotic species, the serine/threonine-specific Polo-like kinase 1 (Plk1) is highly expressed in malignant cells and serves as a negative prognostic marker in specific human cancer types . Here, we report the discovery of a potent small-molecule inhibitor of mammalian Plk1, BI 2536, which inhibits Plk1 enzyme activity at low nanomolar concentrations. The compound potently causes a mitotic arrest and induces apoptosis in human cancer cell lines of diverse tissue origin and oncogenome signature. BI 2536 inhibits growth of human tumor xenografts in nude mice and induces regression of large tumors with well-tolerated intravenous dose regimens. In treated tumors, cells arrest in prometaphase, accumulate phosphohistone H3, and contain aberrant mitotic spindles. This mitotic arrest is followed by a surge in apoptosis, detectable by immunohistochemistry and noninvasive optical and magnetic resonance imaging. For addressing the therapeutic potential of Plk1 inhibition, BI 2536 has progressed into clinical studies in patients with locally advanced or metastatic cancers.Current Biology 03/2007; 17(4):316-22. · 9.65 Impact Factor -
Article: Tumor targeting properties of monoclonal antibodies with different affinity for target antigen CD44V6 in nude mice bearing head-and-neck cancer xenografts.
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ABSTRACT: The CD44 protein family consists of isoforms with tissue-specific expression, which are encoded by standard exons and up to 9 alternatively spliced variant exons (v2-v10) of the same gene. The murine MAbs U36 and BIWA-1, directed against overlapping epitopes within the v6 region of CD44, have previously been shown to efficiently target HNSCC. We herein report on the construction of 1 chimeric (BIWA-2) and 2 humanized (BIWA-4 and BIWA-8) derivatives of BIWA-1. Together with U36 and BIWA-1, these new antibodies were evaluated for affinity to the antigen in vitro as well as for biodistribution and efficacy in RIT using nude mice bearing the HNSCC xenograft line HNX-OE. As determined by surface plasmon resonance, the MAbs bound to CD44v6 with an up to 46-fold difference in affinity (K(d) ranging from 1.1 x 10(-8) to 2.4 x 10(-10) M) with the following ranking: mMAb U36 < hMAb BIWA-4 < hMAb BIWA-8 < mMAb BIWA-1 approximately cMAb BIWA-2. To evaluate their in vivo tumor-targeting properties, 2 MAbs with identical murine or human isotype were labeled with either (131)I or (125)I and administered simultaneously (50 microg/10 microCi each) as pairs showing a stepwise decrease in the difference in affinity: U36 vs. BIWA-1 (35.0-fold difference), BIWA-4 vs. BIWA-2 (14.0-fold) and BIWA-4 vs. BIWA-8 (4.0-fold). Biodistribution was assessed at 1, 2, 3 or 4 and 7 days after injection. Remarkably, for all 3 MAb pairs tested, the lower-affinity MAb showed a higher degree and specificity of tumor localization. The difference in tumor localization was more pronounced when the difference in affinity was larger. For example, 3 days after injection, the lower-affinity mMAb U36 showed a 50% higher tumor uptake than the higher-affinity mMAb BIWA-1, while blood levels and uptake in organs were similar. After labeling with (186)Re (300 or 400 microCi), the same MAb pairs showed RIT efficacy consistent with the biodistribution data: (186)Re-U36 was more effective than (186)Re-BIWA-1, (186)Re-BIWA-4 was slightly more effective than (186)Re-BIWA-2 and (186)Re-BIWA-4 and (186)Re-BIWA-8 demonstrated similar efficacy. Based on these data, we conclude that antibodies with markedly lower affinity to a given target antigen (e.g., U36, BIWA-4) may show superior tumor targeting in comparison with higher-affinity versions of these antibodies.International Journal of Cancer 05/2002; 99(3):396-402. · 5.44 Impact Factor -
Article: Identification and characterization of 9D7, a novel human protein overexpressed in renal cell carcinoma.
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ABSTRACT: With the objective of discovering novel tumor-associated antigens of the cancer/testis type, we compared the transcriptional profiles of renal cell carcinoma (RCC) and non-tumorous kidney and further screened for genes expressed in RCC and testis, but not other normal tissues. In a first step, a representational difference analysis library consisting of approximately 1,900 RCC cDNA clones was generated. Clones were then spotted onto filters and hybridized with cDNA probes derived from a testis-specific cDNA library, a pool of RCCs and a pool of 10 healthy normal tissues, respectively. Based on strong hybridization signals with both RCC and testis, but not normal tissue probes, 185 clones were sequenced and annotated. After EST-database comparison, 35 clones were selected for experimental analysis, including conventional and quantitative RT-PCR as well as Northern blotting. Clone 9D7 showed strong mRNA expression in RCC as well as in several other major tumor types. In normal tissues there was little or no mRNA expression with the exception of heart. 9D7 was cloned to full-size and found to represent a novel human gene containing 5 exons residing on chromosome 14. Alternative splicing within exon 1 generates 2 open-reading-frames consisting of 717 or 435 bp corresponding to predicted proteins of 239 or 145 amino acids. 9D7 shows high homology (227/239 amino acids or 95% identity) to a growth factor-inducible gene of Rattus norvegicus involved in apoptosis. In situ hybridization as well as immunohistochemical analysis using 9D7-specific antisera confirmed overexpression of 9D7 in RCCs as compared to normal kidney tissue.International Journal of Cancer 02/2002; 97(2):217-24. · 5.44 Impact Factor -
Article: Identification and characterization of 9D7, a novel human protein overexpressed in renal cell carcinoma
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ABSTRACT: With the objective of discovering novel tumor-associated antigens of the cancer/testis type, we compared the transcriptional profiles of renal cell carcinoma (RCC) and non-tumorous kidney and further screened for genes expressed in RCC and testis, but not other normal tissues. In a first step, a representational difference analysis library consisting of approximately 1,900 RCC cDNA clones was generated. Clones were then spotted onto filters and hybridized with cDNA probes derived from a testis-specific cDNA library, a pool of RCCs and a pool of 10 healthy normal tissues, respectively. Based on strong hybridization signals with both RCC and testis, but not normal tissue probes, 185 clones were sequenced and annotated. After EST-database comparison, 35 clones were selected for experimental analysis, including conventional and quantitative RT-PCR as well as Northern blotting. Clone 9D7 showed strong mRNA expression in RCC as well as in several other major tumor types. In normal tissues there was little or no mRNA expression with the exception of heart. 9D7 was cloned to full-size and found to represent a novel human gene containing 5 exons residing on chromosome 14. Alternative splicing within exon 1 generates 2 open-reading-frames consisting of 717 or 435 bp corresponding to predicted proteins of 239 or 145 amino acids. 9D7 shows high homology (227/239 amino acids or 95% identity) to a growth factor-inducible gene of Rattus norvegicus involved in apoptosis. In situ hybridization as well as immunohistochemical analysis using 9D7-specific antisera confirmed overexpression of 9D7 in RCCs as compared to normal kidney tissue. © 2002 Wiley-Liss, Inc.International Journal of Cancer 10/2001; 97(2):217 - 224. · 5.44 Impact Factor
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Institutions
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2001–2002
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Boehringer Ingelheim
Biberach an der Riß, Baden-Wuerttemberg, Germany
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